Wellcome to the PBPath Journal Watch!
This bi-monthly journal watch features exciting recently published pancreas and biliary pathology articles that will provide up to date medical knowledge in our field. These articles will be showcased in several convenient categories, including surgical pathology, cytopathology, and molecular pathology among others. The articles in each category are in no particular order. See the list of journals we search regularly here. Previous months’ issues may be found in our archive and you may see drafts of the upcoming issue here.
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We hope that you will enjoy the new PBPath Journal Watch!
- The differential distributions of ASPM isoforms and their roles in Wnt signaling, cell cycle progression, and pancreatic cancer prognosis
The Journal of pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31465125
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and treatment-resistant malignancy. The lack of pathway-informed biomarkers hampers the development of rational diagnostics or therapies. Recently, the protein abnormal spindle-like microcephaly associated (ASPM) was identified as a novel Wnt and stemness regulator in PDAC, while the pathogenic roles of its protein isoforms remain unclarified. We developed novel isoform-specific antibodies and genetic knockdown (KD) of putative ASPM isoforms, whereby we uncovered that the levels of ASPM isoform 1 (iI) and ASPM-iII are variably up-regulated in PDAC cells. ASPM isoforms show remarkably different subcellular locations; specifically, ASPM-iI is exclusively localized to the cortical cytoplasm of PDAC cells while ASPM-iII is predominantly expressed in cell nuclei. Mechanistically, ASPM-iI colocalizes with disheveled-2 and active β-catenin as well as the stemness marker aldehyde dehydrogenase-1 (ALDH-1), and its expression is indispensable for the Wnt activity, stemness and the tumorigenicity of PDAC cells. By contrast, ASPM-iII selectively regulates the expression level of cyclin E and cell cycle progression in PDAC cells. The expression of ASPM-iI and ASPM-iII display considerable intratumoral heterogeneity in PDAC tissues and only that of ASPM-iI was prognostically significant; it outperformed ALDH-1 staining and clinico-pathological variables in a multivariant analysis. Collectively, the distinct expression patterns and biological functions of ASPM isoforms may illuminate novel molecular mechanisms and prognosticators in PDAC and may pave the road for the development of therapies targeting this novel oncoprotein. This article is protected by copyright. All rights reserved.
doi: https://doi.org/10.1002/path.5341
- Chronic inflammation markers are associated with risk of pancreatic cancer in the Swedish AMORIS cohort study
BMC cancer 2019 Aug;19(1):858
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31464604
BACKGROUND: Nested case-control studies examining the association between serum markers of chronic inflammation, focused on three specific biomarkers (CRP, IL-8 and TNF-α), and risk of pancreatic cancer have reported no associations. In this study, we evaluated associations between standard pre-diagnostic serum markers of chronic inflammation (CRP, albumin, haptoglobin and leukocytes) and pancreatic cancer risk in the Swedish Apolipoprotein-related MORtality RISk (AMORIS) prospective cohort study. METHODS: We selected all participants (≥20 years old) with baseline measurements of CRP, albumin, haptoglobin and leukocytes between 1985 and 1996 (n = 61,597). Participants were excluded if they had a history of chronic pancreatitis and all individuals were free from pancreatic cancer at baseline. Cox proportional multivariable hazards regression analysis was carried out for medical cut-offs of CRP, albumin, haptoglobin and leukocytes. RESULTS: We observed an increased risk of pancreatic cancer for those individuals with higher levels of serum haptoglobin (≥1.4 g/L), CRP (≥10 mg/L) and leukocytes (≥10 × 109 cells/L) compared to those with haptoglobin levels < 1.4 g/L, CRP levels < 10 mg/L and Leukocyte levels < 10 × 109 cells/L [haptoglobin HR: 2.23 (95% CI 1.72-2.88), CRP HR: 1.32 (95% CI 1.00-1.74), leukocytes HR: 2.20 (95% CI 1.52-3.18)]. No associations were noted for serum albumin. CONCLUSIONS: We found an increased risk of pancreatic cancer associated with pre-diagnostic serum levels of haptoglobin, CRP and leukocytes. Our finding suggests a possible role of chronic inflammation in the aetiology of pancreatic cancer and highlight the need to further investigate this association.
doi: https://doi.org/10.1186/s12885-019-6082-6
- High Co-expression of Large Tenascin C Splice Variants in Stromal Tissue and Annexin A2 in Cancer Cell Membranes is Associated with Poor Prognosis in Pancreatic Cancer
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31463696
BACKGROUND: Pancreatic cancer tissue contains abundant stromal components, including extracellular matrix proteins such as tenascin C (TNC), which exists as large (TNC-L) and non-large splice variants. Here, we examined human pancreatic cancer specimens for the expression of total TNC (TNC-ALL) and TNC-L in the stroma and annexin A2 (ANXA2), a cell surface receptor for TNC, and evaluated their significance as prognostic markers for pancreatic cancer. METHODS: Expression of ANXA2, TNC-ALL, and TNC-L was examined in 106 pancreatic cancer tissues from patients who underwent curative resection and who had not received prior therapy or surgery. Protein expression was measured by immunohistochemistry and scored on a semi-quantitative scale. The relationships between protein expression, clinicopathological factors, and prognosis were evaluated by Cox proportional hazards analysis. RESULTS: TNC-ALL and TNC-L were detected mainly in the stroma, whereas ANXA2 was predominantly expressed in cancer cell membranes. TNC-ALL was also expressed in non-tumor pancreatic tissue. High levels of stromal TNC-L and membranous ANXA2, but not stromal TNC-ALL, were independently associated with cancer progression and poor prognosis. Moreover, high co-expression of stromal TNC-L and membranous ANXA2 was a superior indicator of poor prognosis compared with detection of TNC-ALL, TNC-L, or ANXA2 alone. CONCLUSIONS: Our data suggest that co-expression of stromal TNC-L and membranous ANXA2 is a poor prognostic marker compared with detection of TNC-L or ANXA2 alone for pancreatic cancer patients. Additionally, targeting of crosstalk between stromal TNC and cancer cell ANXA2 could be a promising therapeutic strategy to overcome refractory pancreatic cancer.
doi: https://doi.org/10.1245/s10434-019-07708-x
- Deficits in the Palliative Care Process Measures in Patients with Advanced Pancreatic Cancer Undergoing Operative and Invasive Nonoperative Palliative Procedures
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31463695
BACKGROUND: Given survival measured in months, metrics, such as 30-day mortality, are poorly suited to measure the quality of palliative procedures for patients with advanced cancer. Nationally endorsed process measures associated with high-quality PC include code-status clarification, goals-of-care discussions, palliative-care referral, and hospice assessment. The impact of the performance of these process measures on subsequent healthcare utilization is unknown. METHODS: Administrative data and manual review were used to identify hospital admissions with performance of palliative procedures for advanced pancreatic cancer at two tertiary care hospitals from 2011 to 2016. Natural language processing, a form of computer-assisted abstraction, identified process measures in associated free-text notes. Healthcare utilization was compared using a Cox proportional hazard model. RESULTS: We identified 823 hospital admissions with performance of a palliative procedure. PC process measures were identified in 68% of admissions. Patients with documented process measures were older (66 vs. 63; p = 0.04) and had a longer length of stay (9 vs. 6 days; p < 0.001). In multivariate analysis, patients treated by surgeons were less likely to have PC process measures performed (odds ratio 0.19; 95% confidence interval 0.10-0.37). Performance of PC process measures was associated with decreased healthcare utilization in a Cox proportional hazard model. CONCLUSIONS: PC process measures were not performed in almost one-third of hospital admissions for palliative procedures in patients with advanced pancreatic cancer. Performance of established high-quality process measures for seriously ill patients undergoing palliative procedures may help patients to avoid burdensome, high-intensity care at the end-of-life.
doi: https://doi.org/10.1245/s10434-019-07757-2
- ASO Author Reflections: Formalization of Robotic Central Pancreatectomy Focusing on the Reconstruction of Pancreatic Digestive Continuity
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31463694
doi: https://doi.org/10.1245/s10434-019-07774-1
- Whole-genome sequencing reveals distinct genetic bases for insulinomas and non-functional pancreatic neuroendocrine tumours: leading to a new classification system
Gut 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31462556
OBJECTIVE: Insulinomas and non-functional pancreatic neuroendocrine tumours (NF-PanNETs) have distinctive clinical presentations but share similar pathological features. Their genetic bases have not been comprehensively compared. Herein, we used whole-genome/whole-exome sequencing (WGS/WES) to identify genetic differences between insulinomas and NF-PanNETs. DESIGN: The mutational profiles and copy-number variation (CNV) patterns of 211 PanNETs, including 84 insulinomas and 127 NF-PanNETs, were obtained from WGS/WES data provided by Peking Union Medical College Hospital and the International Cancer Genome Consortium. Insulinoma RNA sequencing and immunohistochemistry data were assayed. RESULTS: PanNETs were categorised based on CNV patterns: amplification, copy neutral and deletion. Insulinomas had CNV amplifications and copy neutral and lacked CNV deletions. CNV-neutral insulinomas exhibited an elevated rate of YY1 mutations. In contrast, NF-PanNETs had all three CNV patterns, and NF-PanNETs with CNV deletions had a high rate of loss-of-function mutations of tumour suppressor genes. NF-PanNETs with CNV alterations (amplification and deletion) had an elevated risk of relapse, and additional DAXX/ATRX mutations could predict an increased relapse risk in the first 2-year period. CONCLUSION: These WGS/WES data allowed a comprehensive assessment of genetic differences between insulinomas and NF-PanNETs, reclassifying these tumours into novel molecular subtypes. We also proposed a novel relapse risk stratification system using CNV patterns and DAXX/ATRX mutations.
doi: https://doi.org/10.1136/gutjnl-2018-317233
- Cell block processing is optimal for assessing endoscopic ultrasound fine needle aspiration specimens of pancreatic mucinous cysts
Journal of clinical pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31462450
AIMS: The cell block technique for assessing endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) specimens from pancreatic mucinous cystic lesions (MCLs) was systematically evaluated for the first time, including comparisons with three traditional methods of assessing such specimens. METHODS: The prospective arm comprised EUS-FNA specimens from EUS-suspected pancreatic MCLs. The retrospective arm comprised EUS-FNA specimens from pancreatic MCLs surgically resected before the study start. For each specimen, these data points were collected: macroscopic likelihood of mucin, cyst fluid carcinoembryonic antigen (CEA) level and presence of mucin in air-dried, direct smears and in cell block preparations. RESULTS: The prospective and retrospective arms of the study comprised 80 and 30 EUS-FNA specimens, respectively. Seven prospective cases led to surgical resections during the study, and therefore, 37 EUS-FNA specimens were confirmed to have originated from MCLs. In the prospective arm, macroscopic mucin was suspected, cyst fluid CEA level exceeded 192 ng/mL, mucin was detected in direct smears and cell block preparations in 78%, 30%, 39% and 73% of cases, respectively. Of the 37 specimens confirmed to originate from MCLs, macroscopic mucin assessment, cyst fluid CEA level, direct smear mucin assessment and cell block mucin assessment had sensitivities for diagnosing MCL of 87%, 45%, 45% and 81%, respectively. CONCLUSIONS: Cell block preparations are as likely to identify mucin from pancreatic MCLs as macroscopic assessment but are twice as likely to diagnose MCL than direct smears and fluid CEA biochemistry. The cell block technique is easy for sample collection and processing especially because these are identical for solid and cystic pancreatic lesions.
doi: https://doi.org/10.1136/jclinpath-2019-206079
- Pancreatic calcifications associate with diverse aetiological risk factors in patients with chronic pancreatitis: A multicentre study of 1500 cases
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31462382
BACKGROUND: Pancreatic calcifications is a common finding in patients with chronic pancreatitis (CP), but the underlying pathophysiology is incompletely understood. Past studies for risk factors of calcifications have generally been focused on single parameters or limited by small sample sizes. The aim of this study was to explore several patient and disease characteristics and their associations with pancreatic calcifications in a large cohort of CP patients with diverse aetiological risk factors. METHODS: This was a multicentre, cross-sectional study including 1509 patients with CP. Patient and disease characteristics were compared for patients with calcifications (n = 912) vs. without calcifications (n = 597). Multivariable logistic regression was performed to assess the parameters independently associated with calcifications. RESULTS: The mean age of patients was 53.9 ± 14.5 years and 1006 (67%) were men. The prevalence of calcifications was 60.4% in the overall patient cohort, but highly variable between patients with different aetiological risk factors (range: 2-69%). On multivariate analysis, alcoholic aetiology (OR 1.76 [95% CI, 1.39-2.24]; p < 0.001) and smoking aetiology (OR 1.77 [95% CI, 1.39-2.26], p < 0.001) were positively associated with the presence of calcifications, while an autoimmune aetiology was negatively associated with calcifications (OR 0.15 [95% CI, 0.08-0.27], p < 0.001). Patients with pancreatic calcifications were more likely to have undergone pancreatic duct stenting (OR 1.59 [95%CI, 1.16-2.19], p = 0.004). CONCLUSION: The presence of pancreatic calcifications is associated with diverse aetiological risk factors in patients with CP. This observation attest to the understanding of CP as a complex disease and may have implications for disease classification.
doi: https://doi.org/10.1016/j.pan.2019.08.009
- Comparative efficacy and tolerability of front-line treatments for newly diagnosed chronic-phase chronic myeloid leukemia: an update network meta-analysis
BMC cancer 2019 Aug;19(1):849
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31462241
BACKGROUND: Recent years have witnessed the rapid evolution of therapies in chronic-phase chronic myeloid leukemia (CP-CML). To assess the efficacy and tolerability of all reported front-line treatments for patients with newly diagnosed CML, a multiple-treatments meta-analysis was performed, which accounted for both direct and indirect comparisons among those treatments. METHODS: Primary outcomes were the percentage of patients achieving major molecular response (MMR) and complete cytogenetic response (CCyR) within 12 months. Secondary outcomes included the percentage of progression to accelerated phase (AP), serious adverse effects (AEs), overall discontinuation and discontinuation for drug-related AEs. Direct pairwise meta-analysis and indirect multi-comparison meta-analysis among those treatments in each outcome were both conducted. The surface under the cumulative ranking curve (SUCRA) was calculated for all treatments in each outcome. Cluster analysis demonstrated the division of treatments into distinct groupings according to efficacy and tolerability profiles. RESULTS: A total of 21 randomized controlled trials (RCTs, including 10,187 patients) comparing 15 different interventions for CP-CML patients were included in this study. SUCRA analysis suggested that all tyrosine kinase inhibitors (TKIs) are highly effective in newly diagnosed CP-CML when compared to traditional drugs. Newer TKIs and higher-dose imatinib generally resulted in faster cytogenetic and molecular responses when compared with standard-dose imatinib and traditional drugs. Furthermore, traditional drugs, higher-dose imatinib and newer TKIs demonstrated lower acceptability than standard-dose imatinib. One cluster of interventions, which included nilotinib (300/400 mg BID), dasatinib (100 mg QD) and radotinib (300 mg BID), demonstrated higher efficacy and tolerability than other treatments. CONCLUSIONS: Nilotinib (300/400 mg BID), dasatinib (100 mg QD) and radotinib (300 mg BID) prove to be the most recommended front-line treatments of the greatest efficacy and tolerability for CP-CML patients. High-dose therapies are recommended only for patients in accelerated phase/blast phase or with suboptimal CML-CP response, and management of adverse events should be carried out to avoid compromising the clinical efficacy.
doi: https://doi.org/10.1186/s12885-019-6039-9
- Preoperative Risk Assessment for Loss of Independence Following Hepatic Resection in Elderly Patients: A Prospective Multicenter Study
Annals of surgery 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31460876
OBJECTIVE: To establish a preoperative risk assessment method for loss of independence after hepatic resection. SUMMARY BACKGROUND DATA: Hepatic resection often results in loss of independence in preoperatively self-sufficient elderly people. Elderly patients should therefore be carefully selected for surgery. METHODS: In this prospective, multicenter study, 347 independently-living patients aged ≥65 years, scheduled for hepatic resection, were divided into study (n = 232) and validation (n = 115) cohorts. We investigated the risk factors for postoperative loss of independence in the study cohort and verified our findings with the validation cohort. Loss of independence was defined as transfer to a rehabilitation facility, discharge to residence with home-based healthcare, 30-day readmission for poor functionality, and 90-day mortality (except for cancer-related deaths). RESULTS: In the study cohort, univariate and multivariate analyses indicated that frailty, age ≥ 76 years, and open surgery were independent risk factors for postoperative loss of independence. Proportions of patients with postoperative loss of independence in the study and validation cohorts were respectively 3.0% and 0% among those with no applicable risk factors, 8.1% and 12.5% among those with 1 applicable risk factor, 25.5% and 25.0% among those with 2 applicable risk factors, and 56.3% and 50.0% among those with all 3 factors applicable (P < 0.001 for both cohorts). Areas under the receiver operating characteristic curves for the study and validation groups were 0.777 and 0.783, respectively. CONCLUSIONS: Preoperative risk assessments using these 3 factors may be effective in predicting and planning for postoperative loss of independence after hepatic resection in elderly patients.
doi: https://doi.org/10.1097/SLA.0000000000003585
- An analysis of genetic heterogeneity in untreated cancers
Nature reviews. Cancer 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31455892
Genetic intratumoural heterogeneity is a natural consequence of imperfect DNA replication. Any two randomly selected cells, whether normal or cancerous, are therefore genetically different. Here, we review the different forms of genetic heterogeneity in cancer and re-analyse the extent of genetic heterogeneity within seven types of untreated epithelial cancers, with particular regard to its clinical relevance. We find that the homogeneity of predicted functional mutations in driver genes is the rule rather than the exception. In primary tumours with multiple samples, 97% of driver-gene mutations in 38 patients were homogeneous. Moreover, among metastases from the same primary tumour, 100% of the driver mutations in 17 patients were homogeneous. With a single biopsy of a primary tumour in 14 patients, the likelihood of missing a functional driver-gene mutation that was present in all metastases was 2.6%. Furthermore, all functional driver-gene mutations detected in these 14 primary tumours were present among all their metastases. Finally, we found that individual metastatic lesions responded concordantly to targeted therapies in 91% of 44 patients. These analyses indicate that the cells within the primary tumours that gave rise to metastases are genetically homogeneous with respect to functional driver-gene mutations, and we suggest that future efforts to develop combination therapies have the potential to be curative.
doi: https://doi.org/10.1038/s41568-019-0185-x
- A phase 1 study of the anti-CC chemokine receptor 4 antibody, mogamulizumab, in combination with nivolumab in patients with advanced or metastatic solid tumors
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31455681
PURPOSE: Regulatory T-cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab (anti-programmed death-1 [PD-1] antibody) in immunotherapy-naive patients with advanced/metastatic solid tumors. EXPERIMENTAL DESIGN: This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose-escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted. RESULTS: 96 patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculo-papular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4+CD45RA-FoxP3high) decreased and CD8+ T-cells in tumor-infiltrating lymphocytes increased. CONCLUSIONS: Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy.
doi: https://doi.org/10.1158/1078-0432.CCR-19-1090
- Allosteric modulation of ��-cell M3 muscarinic acetylcholine receptors greatly improves glucose homeostasis in lean and obese mice
Proceedings of the National Academy of Sciences of the United States of America 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31451647
Given the global epidemic in type 2 diabetes, novel antidiabetic drugs with increased efficacy and reduced side effects are urgently needed. Previous work has shown that M3 muscarinic acetylcholine (ACh) receptors (M3Rs) expressed by pancreatic β cells play key roles in stimulating insulin secretion and maintaining physiological blood glucose levels. In the present study, we tested the hypothesis that a positive allosteric modulator (PAM) of M3R function can improve glucose homeostasis in mice by promoting insulin release. One major advantage of this approach is that allosteric agents respect the ACh-dependent spatiotemporal control of M3R activity. In this study, we first demonstrated that VU0119498, a drug known to act as a PAM at M3Rs, significantly augmented ACh-induced insulin release from cultured β cells and mouse and human pancreatic islets. This stimulatory effect was absent in islets prepared from mice lacking M3Rs, indicative of the involvement of M3Rs. VU0119498 treatment of wild-type mice caused a significant increase in plasma insulin levels, accompanied by a striking improvement in glucose tolerance. These effects were mediated by β-cell M3Rs, since they were absent in mutant mice selectively lacking M3Rs in β cells. Moreover, acute VU0119498 treatment of obese, glucose-intolerant mice triggered enhanced insulin release and restored normal glucose tolerance. Interestingly, doses of VU0119498 that led to pronounced improvements in glucose homeostasis did not cause any significant side effects due to activation of M3Rs expressed by other peripheral cell types. Taken together, the data from this proof-of-concept study strongly suggest that M3R PAMs may become clinically useful as novel antidiabetic agents.
doi: https://doi.org/10.1073/pnas.1904943116
- “Trivial” Cysts Redefine the Risk of Cancer in Presumed Branch-Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas: A Potential Target for Follow-Up Discontinuation?
The American journal of gastroenterology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31449158
OBJECTIVES: The management of small and incidental branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) still is of concern. The aim is assessing the safety of a surveillance protocol through the evaluation of their progression to malignancy. METHODS: All presumed BD-IPMNs observed from 2000 to 2016 were included. Only patients presenting without worrisome features (WFs) and high-risk stigmata (HRS) at diagnosis were included. Development of WF, HRS, pancreatic cancer (PC), and survival were analyzed. BD-IPMNs were defined as trivial in the continuing absence of WF/HRS after 5 years of surveillance. The age-specific standardized incidence ratio of PC in the general population was used for comparison. RESULTS: A total of 1,036 BD-IPMNs without WF/HRS at diagnosis were included, 4.2% developed WF or HRS, and 1.1% developed PC after a median of 62 months. The median cyst growth rate was 0 mm/yr. A growth rate ≥2.5 mm/yr and the development of WF resulted independent predictors of PC. The standardized incidence ratio of PC for trivial BD-IPMN (n = 378) was 22.45 (95% confidence interval 8.19-48.86), but considering only patients aged >65 years (n = 198), it decreased to 3.84 (95% confidence interval 0.77-11.20). DISCUSSION: Surveillance of the vast majority of presumed BD-IPMNs is safe, as the risk of PC is comparable to postoperative mortality of pancreatic surgery. A growth rate ≥2.5 mm/yr is the main predictor of PC, reinforcing the role of repeated observations. A trivial BD-IPMN in patients aged >65 years might not increase the risk of developing PC compared with general population, identifying potential targets for follow-up discontinuation.
doi: https://doi.org/10.14309/ajg.0000000000000378
- Management of Locally Advanced Pancreatic Cancer: Results of an International Survey of Current Practice
Annals of surgery 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31449138
MINI: An international survey of high-volume pancreas cancer surgeons revealed wide variations in management preferences, attitudes regarding contraindications to surgery, and the propensity to offer exploration. When presented with 6 hypothetical clinical vignettes using details from real patients that have received R0 resection, only 14% to 53% of participating surgeons were willing to offer exploration following neoadjuvant therapy. The aim of this study was to investigate surgeon preferences for the management of patients with locally advanced pancreatic cancer (LAPC). Select patients with LAPC may become candidates for curative resection following neoadjuvant therapy, and recent reports of survival are encouraging. Yet the optimal management approach remains unclear. An extensive electronic survey was systematically distributed by email to an international cohort of pancreas surgeons. Data collected included practice characteristics, management preferences, attitudes regarding contraindications to surgery, and 6 clinical vignettes of patients that ultimately received a margin negative resection (with detailed videos of post-neoadjuvant imaging) to assess propensity for surgical exploration if resection status is not known. A total of 153 eligible responses were received from 4 continents. Median duration of practice is 12 years (interquartile range 6-20) and 77% work in a university setting. Most surgeons (86%) are considered high volume (>10 resections/yr), 33% offer a minimally-invasive approach, and 50% offer arterial resections in select patients. Most (72%) always recommend neoadjuvant chemotherapy, and 65% prefer FOLFIRINOX. Preferences for the duration of chemotherapy varied widely: 39% prefer ≥2 months, 43% prefer ≥4 months, and 11% prefer ≥6 months. Forty-one percent frequently recommend neoadjuvant radiotherapy, and 53% prefer 5 to 6 weeks of chemoradiation. The proportion of surgeons favoring exploration following neoadjuvant varied extensively across 5 vignettes of LAPC, from 14% to 53%. In a vignette of oligometastatic liver metastases, 31% would offer exploration if a favorable therapy response is observed. In an international cohort of pancreas surgeons, there is substantial variation in management preferences, perceived contraindications to surgery, and the propensity to consider exploration in LAPC. These results emphasize the importance of a robust and nuanced multidisciplinary discussion for each patient, and suggest an evolving concept of “resectability.”
doi: https://doi.org/10.1097/SLA.0000000000003568
- Obesity and pancreatic cancer: An update of epidemiological evidence and molecular mechanisms
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31447281
Despite advances in therapy and achievements in translational research, pancreatic cancer (PC) remains an invariably fatal malignancy. Risk factors that affect the incidence of PC include diabetes, smoking, obesity, chronic pancreatitis, and diet. The growing worldwide obesity epidemic is associated with an increased risk of the most common cancers, including PC. Chronic inflammation, hormonal effects, circulating adipokines, and adipocyte-mediated inflammatory and immunosuppressive microenvironment are involved in the association of obesity with PC. Herein, we systematically review the epidemiology of PC and the biological mechanisms that may account for this association. Included in this review is a discussion of adipokine-mediated inflammation, lipid metabolism, and the interactions of adipocytes with cancer cells. We consider the influence of bariatric surgery on the risk of PC risk as well as potential molecular targets of therapy. Our review leads us to conclude that targeting adipose tissue to achieve weight loss may represent a new therapeutic strategy for preventing and treating PC.
doi: https://doi.org/10.1016/j.pan.2019.08.008
- ESWL for large pancreatic calculi: Report of over 5000 patients
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31447280
INTRODUCTION: The primary aim of this study was to evaluate efficacy, safety and short-term pain relief after ESWL for large pancreatic calculi in over 5000 patients at a single center. METHODS: This is a retrospective analysis of prospectively collected data. Patients with painful calculi >5 mm, located in the head, neck and body region in the MPD, who were not amenable for extraction by the standard procedure of endoscopic pancreatic sphincterotomy were subjected to ESWL using a third generation dual focus lithotripter. Patients were followed up at 6 months for outcome evaluation. RESULTS: A total of 5124 patients (66% males) were subjected to ESWL. Majority of stones (79.2%) were radiopaque. Single calculi were seen in 3851 (75.1%).The majority of stones were located in head region of MPD in 2824 (55.1%) patients. 4386 (85.5%) patients required 3 or less sessions for fragmentation and complete stone clearance was achieved in 3722 (72.6%). EPS was performed in 5022 (98%) while PD stenting was required in 3536 (69%) patients. Of the 4280 patients followed up for 6 months, 3529 (82.6%) patients were pain free. Another 512 (11.9%) patients had significant reduction in VAS score. In 229 (5.3%) there was no decrease in pain intensity. Minor and self-limiting complications were reported in 1153 (22.5%). DISCUSSION: Our study confirms the safety and efficacy and short-term pain relief of ESWL for large calculi in the MPD. In properly selected patients, this should be offered as the first line of therapy for all large MPD calculi not amenable to the standard techniques of stone extraction.
doi: https://doi.org/10.1016/j.pan.2019.08.001
- New High-throughput Screen Identifies Compounds That Reduce Viability Specifically In Liver Cancer Cells That Express High Levels of SALL4 by Inhibiting Oxidative Phosphorylation
Gastroenterology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31446059
BACKGROUND AND AIMS: Some oncogenes encode transcription factors, but few drugs have been successfully developed to block their activity specifically in cancer cells. The transcription factor SALL4 is aberrantly expressed in solid tumor and leukemia cells. We developed a screen to identify compounds that reduce the viability of liver cancer cells that express high levels of SALL4 and we investigated their mechanisms. METHODS: We developed a stringent high-throughput screening platform comprising unmodified SNU-387 and SNU-398 liver cancer cell lines and SNU-387 cell lines engineered to express low and high levels of SALL4. We screened 1597 pharmacologically active small molecules and 21,575 natural product extracts from plant, bacteria, and fungal sources for those that selectively reduce the viability of cells with high levels of SALL4 (SALL4hi cells). We compared gene expression patterns of SALL4hi cells vs SALL4-knockdown cells using RNA-seq and real-time PCR analyses. Xenograft tumors were grown in NOD/SCID gamma mice from SALL4hi SNU-398 or HCC26.1 cells or from SALL4lo PDX cells; mice were given injections of identified compounds or sorafenib and the effects on tumor growth were measured. RESULTS: Our screen identified 1 small molecule (PI-103) and 4 natural compound analogues (oligomycin, efrapeptin, antimycin, and leucinostatin) that selectively reduced viability of SALL4hi cells. We performed validation studies, and 4 of these compounds were found to inhibit oxidative phosphorylation. The ATP synthase inhibitor oligomycin reduced the viability of SALL4hi hepatocellular carcinoma and non-small-cell lung cancer cell lines with minimal effects on SALL4lo cells. Oligomycin also reduced the growth of xenograft tumors grown from SALL4hi SNU-398 or HCC26.1 cells, to a greater extent than sorafenib, but oligomycin had little effect on tumors grown from SALL4lo PDX cells. Oligomycin was not toxic to mice. Analyses of chromatin immunoprecipitation sequencing data revealed that SALL4 binds approximately 50% of mitochondrial genes, including many oxidative phosphorylation genes, to activate their transcription. In comparing SALL4hi and SALL4-knockdown cells, we found SALL4 to increase oxidative phosphorylation, oxygen consumption rate, mitochondrial membrane potential, and utilization of oxidative phosphorylation-related metabolites to generate ATP. CONCLUSIONS: In a screen for compounds that reduce the viability of cells that express high levels of the transcription factor SALL4, we identified inhibitors of oxidative phosphorylation, which slowed the growth of xenograft tumors from SALL4hi cells in mice. SALL4 activates transcription of genes that regulate oxidative phosphorylation to increase oxygen consumption, mitochondrial membrane potential, and ATP generation in cancer cells. Inhibitors of oxidative phosphorylation might be used for treatment of liver tumors with high levels of SALL4.
doi: https://doi.org/10.1053/j.gastro.2019.08.022
- A rational approach to postoperative surveillance for resected non-functional pancreatic neuro-endocrine tumours
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31445889
BACKGROUND: Non-functional pancreatic neuroendocrine tumours (NF-PNETs) are rare and have highly variable outcomes. Current guidelines recommend surveillance for NF-PNETs <2 cm. Patients who ultimately have surgical resection are at risk of disease recurrence, and data to support postoperative surveillance protocols are lacking. The aims of this study were to i) identify post-operative predictors of recurrence and ii) risk stratify patients at risk of recurrence. METHODS: Consecutive patients who underwent surgery for NF-PNETs between 2002 and 2015 were identified retrospectively. Data were collected on demographics, pre-operative laboratory results and histopathological tumour characteristics. Statistical analyses were based on penalised Cox-regression modelling and a decision-tree model. Comparison of the variables identified was performed using ROC curves to identify the most sensitive and specific variable associated with disease recurrence. RESULTS: We identified 73 patients (38 males) with a median age of 61.5 years (range: 31-79). The median period of follow-up was 49 months (5-131). During follow up, 10 deaths (13.9%) were recorded and disease recurrence occurred in 12 patients (16.4%). The Kaplan-Meier predicted 1-,3- and 5-year recurrence-free survival rates were 98.6% (95% CI = 95.9, 100%), 85.4% (76.9-94.8%) and 72% (58.7-88.2%) respectively. Cox multivariate analysis identified poor tumour differentiation (WHO G3 grade) and lymph node ratio (LNR) as independent predictors for recurrence (p < 0.05). A simple criterion of ‘tumour grade G3 or LNR ≥0.1’ was found to be sensitive and specific in detecting disease recurrence. CONCLUSION: Our results have identified a simple and sensitive criterion for risk stratifying post-resection surveillance. Prospective validation in larger patient cohort is now warranted.
doi: https://doi.org/10.1016/j.pan.2019.08.005
- Design of an immunohistochemistry biomarker panel for diagnosis of pancreatic adenocarcinoma
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31445888
BACKGROUND: Challenges still exist in differentiating pancreatic adenocarcinoma from benign disease. The use of adjuvant testing of tissue biopsies has demonstrated potential diagnostic value. We designed a proof of concept study to first validate four individual immunohistochemistry biomarkers and then combine them into a panel to boost overall diagnostic sensitivity. METHODS: Malignant and benign pancreas from 27 pancreaticoduodenectomy specimens underwent immunohistochemistry staining with VHL, IMP3, S100A4, S100P. Using ROC curve analysis, threshold criteria for number of cells staining were chosen for each biomarker. Biomarkers were then evaluated as a panel for their ability to discriminate malignant from benign specimens. RESULTS: Diagnostic sensitivity of VHL, IMP3, S100A4, and S100P were 75.0%, 79.2%, 45.8%, and 0%. When VHL, IMP3, and S100A4 were grouped into a panel, they were able to distinguish cancer from normal tissue with a sensitivity of 100% and a specificity of 96%. CONCLUSIONS: The high diagnostic value of an IHC panel consisting of VHL, IMP3, and S100A4 on surgical specimens suggests the need for future prospective studies of these biomarkers on biopsy specimens.
doi: https://doi.org/10.1016/j.pan.2019.08.007
- Primary pancreatic diffuse large B-cell lymphoma diagnosed by endoscopic ultrasound guided FNAC: A rare entity
Diagnostic cytopathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31444945
Primary pancreatic lymphoma (PPL) is an uncommon neoplasm which can clinico-radiologically mimic carcinoma. But the management of these patients differs from that of a carcinoma. Endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA) serves as a potential tool to identify pancreatic lymphomas and thus prevent an invasive diagnostic test. This case report describes the presentation and diagnosis of primary pancreatic lymphoma. A 37-year-old female presented with nausea, vomiting with signs of icterus and elevated liver function test and Bilirubin. Abdominal computed tomography (CT) revealed a hypodense lesion in the head of the pancreas. EUS guided FNA was performed and cytological material was collected. The lesion was diagnosed as Non-Hodgkin Lymphoma (NHL) and subtyped as diffuse large B-cell lymphoma-germinal centre (DLBCL-GCB) base on immunohistochemistry on cell block. The patient was started on rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (RCHOP) regimen. EUS guided FNA along with ROSE, cell bock, and immunocytochemistry helps in the diagnosis of primary pancreatic lymphoma.
doi: https://doi.org/10.1002/dc.24307
- Medium and long-term risks of specific cardiovascular diseases in survivors of 20 adult cancers: a population-based cohort study using multiple linked UK electronic health records databases
Lancet (London, England) 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31443926
BACKGROUND: The past few decades have seen substantial improvements in cancer survival, but concerns exist about long-term cardiovascular disease risk in survivors. Evidence is scarce on the risks of specific cardiovascular diseases in survivors of a wide range of cancers to inform prevention and management. In this study, we used large-scale electronic health records data from multiple linked UK databases to address these evidence gaps. METHODS: For this population-based cohort study, we used linked primary care, hospital, and cancer registry data from the UK Clinical Practice Research Datalink to identify cohorts of survivors of the 20 most common cancers who were 18 years or older and alive 12 months after diagnosis and controls without history of cancer, matched for age, sex, and general practice. We compared risks for a range of cardiovascular disease outcomes using crude and adjusted Cox models. We fitted interactions to investigate effect modification, and flexible parametric survival models to estimate absolute excess risks over time. FINDINGS: Between Jan 1, 1990, and Dec 31, 2015, 126 120 individuals with a diagnosis of a cancer of interest still being followed up at least 1 year later were identified and matched to 630 144 controls. After exclusions, 108 215 cancer survivors and 523 541 controls were included in the main analyses. Venous thromboembolism risk was elevated in survivors of 18 of 20 site-specific cancers compared with that of controls; adjusted hazard ratios (HRs) ranged from 1·72 (95% CI 1·57-1·89) in patients after prostate cancer to 9·72 (5·50-17·18) after pancreatic cancer. HRs decreased over time, but remained elevated more than 5 years after diagnosis. We observed increased risks of heart failure or cardiomyopathy in patients after ten of 20 cancers, including haematological (adjusted HR 1·94, 1·66-2·25, with non-Hodgkin lymphoma; 1·77, 1·50-2·09, with leukaemia; and 3·29, 2·59-4·18, with multiple myeloma), oesophageal (1·96, 1·46-2·64), lung (1·82, 1·52-2·17) kidney (1·73, 1·38-2·17) and ovarian (1·59, 1·19-2·12). Elevated risks of arrhythmia, pericarditis, coronary artery disease, stroke, and valvular heart disease were also observed for multiple cancers, including haematological malignancies. HRs for heart failure or cardiomyopathy and venous thromboembolism were greater in patients without previous cardiovascular disease and in younger patients. However, absolute excess risks were generally greater with increasing age. Increased risks of these outcomes seemed most pronounced in patients who had received chemotherapy. INTERPRETATION: Survivors of most site-specific cancers had increased medium-term to long-term risk for one or more cardiovascular diseases compared with that for the general population, with substantial variations between cancer sites. FUNDING: Wellcome Trust and Royal Society.
doi: https://doi.org/10.1016/S0140-6736(19)31674-5
- The Histone Demethylase KDM3A, Increased in Human Pancreatic Tumors, Regulates Expression of DCLK1 in and Promotes Tumorigenesis in Mice
Gastroenterology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31442435
BACKGROUND & AIMS: The histone lysine demethylase 3A (KDM3A) demethylates demethylates H3K9me1 and H3K9Me2 to increase gene transcription and is upregulated in tumors, including pancreatic tumors. We investigated its activities in pancreatic cancer cell lines and its regulation of the gene encoding doublecortin calmodulin-like kinase 1 (DCLK1), a marker of cancer stem cells. METHODS: We knocked down KDM3A in MiaPaCa-2 and S2-007 pancreatic cancer cell lines and overexpressed KDM3A in HPNE cells (a human pancreatic cell line); we evaluated cell migration, invasion, and spheroid formation under hypoxic and normoxic conditions. Nude mice were given orthotopic injections of S2-007 cells, with or without (control) knockdown of KDM3A, and HPNE cells, with or without (control) overexpression of KDM3A; tumor growth was assessed. We analyzed pancreatic tumor tissues from mice and pancreatic cancer cell lines by immunohistochemistry and immunoblotting. We performed RNA-seq analysis of MiaPaCa-2 and S2-007 cells with knockdown of KDM3A and evaluated localization of DCLK1 and KDM3A by immunofluorescence. We analyzed the cancer genome atlas for levels of KDM3A and DCLK1 mRNA in human pancreatic ductal adenocarcinoma (PDAC) tissues and association with patient survival time. RESULTS: Levels of KDM3A were increased in human pancreatic tumor tissues and cell lines, compared with adjacent non-tumor pancreatic tissues such as islet and acinar cells. Knockdown of KDM3A in S2-007 cells significantly reduced colony formation, invasion, migration, and spheroid formation, compared with control cells, and slowed growth of orthotopic tumors in mice. We identified KDM3A-binding sites in the DCLK1 promoter; S2-007 cells with knockdown of KDM3A had reduced levels of DCLK1. HPNE cells that overexpressed KDM3A formed foci and spheres in culture and formed tumors and metastases in mice, whereas control HPNE cells did not. Hypoxia induced sphere formation and increased levels of KDM3A in S2-007 cells and in HPNE cells that overexpressed DCLK1, but not control HPNE cells. Levels of KDM3A and DCLK1 mRNA were higher in human PDAC than non-tumor pancreatic tissues and correlated with shorter survival times of patients. CONCLUSIONS: We found human PDAC samples and pancreatic cancer cell lines to overexpress KDM3A. KDM3A increases expression of DCLK1, and levels of both proteins are increased in human PDAC samples. Knockdown of KDM3A in in pancreatic cancer cell lines reduced their invasive and sphere-forming activities in culture and formation of orthotopic tumors in mice. Hypoxia increased expression of KDM3A in pancreatic cancer cells. Strategies to disrupt this pathway might be developed for treatment of pancreatic cancer.
doi: https://doi.org/10.1053/j.gastro.2019.08.018
- Dynamic Changes in Normal Liver Parenchymal Volume During Chemotherapy for Colorectal Cancer: Liver Atrophy as an Alternate Marker of Chemotherapy-Associated Liver Injury
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31440929
BACKGROUND: The purpose of this study was to investigate the incidence, origin, and clinical significance of liver atrophy during chemotherapy for colorectal cancer. METHODS: This study included 103 patients who underwent chemotherapy before resection for colorectal liver metastases (training set) and 171 patients who underwent adjuvant or first-line chemotherapy without liver resection (validation set). A greater than 10% decrease (atrophy) or increase (hypertrophy) of the liver volume from the baseline was defined as a significant change. RESULTS: In the training set, the numbers of patients who developed atrophy, no change of volume, and hypertrophy of the liver after chemotherapy were 15 (14.6%), 73 (70.9%), and 15 (14.6%), respectively. Liver atrophy was associated with impaired hepatic function, and the postoperative morbidity rate and refractory ascites/pleural effusion were higher in the patients with liver atrophy than those without (60.0% vs. 31.8%, P = 0.045 and 46.7% vs. 8.0%, P < 0.001, respectively). Histopathological examination revealed a strong association between sinusoidal injury and liver atrophy (P < 0.001). The cumulative incidence of liver atrophy increased with increasing duration of chemotherapy, whereas the incidence of liver atrophy was less frequent in patients who had received bevacizumab than those who had not in both the training set (odds ratio [OR], 0.13; P = 0.001) and the validation set (OR, 0.31; P = 0.007). CONCLUSIONS: Liver atrophy is associated with impaired hepatic functional reserve and observed at an increasing frequency as the duration of chemotherapy increases with frequent histopathological evidence of sinusoidal injury in the liver. Bevacizumab may protect against the development of liver atrophy.
doi: https://doi.org/10.1245/s10434-019-07740-x
- A Prospective, Open-Label, Multicenter Phase 2 Trial of Neoadjuvant Therapy Using Full-Dose Gemcitabine and S-1 Concurrent with Radiation for Resectable Pancreatic Ductal Adenocarcinoma
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31440928
BACKGROUND: Neoadjuvant therapy reportedly shows only marginal clinical benefit in pancreatic ductal adenocarcinoma (PDAC), especially in resectable cases. However, with more effective regimens, neoadjuvant therapy may become a standard of care for resectable cases. A prospective, open-label, multicenter phases 1 and 2 trial of neoadjuvant therapy was conducted using full-dose gemcitabine and S-1 concurrently with 50.4 Gy of radiation therapy (GSRT) for resectable PDAC. This report describes the phase 2 results. METHODS: The phase 2 part of this study enrolled 57 patients with cytologically or histologically proven PDAC deemed resectable based on imaging before neoadjuvant therapy. These patients received GSRT. After reevaluation by computed tomography scan, surgical exploration was performed, followed by adjuvant therapy. According to the prescribed protocol of the clinical trial, statistical analyses included 57 phase 2 patients and 6 phase 1 patients who received the same dosage as in phase 2. RESULTS: This trial enrolled 63 patients (42 men and 21 women) with a median age of 70 years. Leukopenia or neutropenia of grade 3 or higher occurred for 79% of the patients, but no other severe adverse events were observed. Among the 63 patients, 54 underwent surgical resection. Intention-to-treat analysis of the 63 patients showed an excellent median survival time lasting as long as 55.3 months. The patients who completed neoadjuvant therapy, surgery, and adjuvant therapy had a 5-year survival rate of 56.6%. CONCLUSIONS: This regimen showed outstanding clinical efficacy with acceptable tolerability for patients with resectable PDAC.
doi: https://doi.org/10.1245/s10434-019-07735-8
- ASO Author Reflections: Lymph Node Metastasis and the Role for Lymphadenectomy During Surgery for Nonfunctional Pancreatic Neuroendocrine Tumors
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31440924
doi: https://doi.org/10.1245/s10434-019-07746-5
- Editorial About: “A Prospective, Open-Label, Multicenter Phase II Trial of Neoadjuvant Therapy Using Full-Dose Gemcitabine and S-1 Concurrent with Radiation for Resectable Pancreatic Ductal Adenocarcinoma”
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31440923
doi: https://doi.org/10.1245/s10434-019-07737-6
- Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma
Proceedings of the National Academy of Sciences of the United States of America 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31439820
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.
doi: https://doi.org/10.1073/pnas.1901323116
- Phase I Trial of Well-Differentiated Neuroendocrine Tumors (NETs) with Radiolabeled Somatostatin Antagonist 177 Lu-Satoreotide Tetraxetan
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31439583
PURPOSE: Radiolabeled somatostatin receptor 2 (SSTR2) antagonists have shown higher tumor uptake and tumor-to-organ ratios than somatostatin agonists in preclinical models of NETs. We performed a phase I study to evaluate the safety and efficacy of SSTR2 antagonist 177Lu-satoreotide tetraxetan. EXPERIMENTAL DESIGN: Twenty patients with advanced SSTR2 positive NETs were treated with 177Lu-satoreotide tetraxetan. Patients first underwent a dosimetry study with 177Lu-satoreotide tetraxetan to determine the therapeutic activity that could be safely administered. This activity was split into two equal cycles to be delivered three months apart. The maximum activity was 7.4 GBq per cycle. RESULTS: Of 20 NET patients (1 lung, 7 small bowel, 9 pancreatic, 1 gastric, 1 rectal, 1 kidney; mean prior treatments: 3), 6 received one cycle of 177Lu- satoreotide tetraxetan and 14 received two cycles. Hematologic toxicity after cycle 1 was mild-moderate and reversed before cycle 2. However, grade 4 hematologic toxicity occurred in 4/7 (57%) patients after cycle 2 of 177Lu-satoreotide tetraxetan. The study was suspended, and the protocol modified to limit the cumulative absorbed bone marrow dose to 1Gy and to reduce prescribed activity for cycle 2 by 50%. The best overall response rate was 45% (5% complete response (1/20), 40% partial response (8/20)); with 40% stable disease (8/20) and 15% progression of disease (3/20). Median progression-free survival (PFS) was 21.0 months (95% CI: 13.6-NR). CONCLUSION: In this trial of heavily treated NETs, preliminary data are promising for the use of 177Lu-satoreotide tetraxetan. Additional studies are on-going to determine optimal therapeutic dose/schedule.
doi: https://doi.org/10.1158/1078-0432.CCR-19-1026
- Ovarian Steroid Cell Tumor in an Adolescent With Von Hippel-Lindau Syndrome: A Case Report and Review of the Literature
International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31433374
Von Hippel-Lindau (VHL) syndrome is an autosomal dominant genetic disorder caused by germline mutation of the VHL gene. It is associated with multiple neoplasias including hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma, and neuroendocrine tumors. Ovarian tumors are extremely rare in this syndrome. We describe the case of a 16-yr-old girl with a previous diagnosis of bilateral pheochromocytoma and several pancreatic neuroendocrine tumors in VHL syndrome context. Follow-up abdominal-pelvic magnetic resonance imaging revealed a 33 mm, well-circumscribed nodule in the right ovary. The patient was submitted to laparoscopic right salpingo-oophorectomy. Microscopically, the tumor consisted of polygonal cells with abundant microvacuolized clear cytoplasm arranged in a solid pattern. The neoplastic cells were immunohistochemically positive for inhibin and calretinin. A diagnosis of ovarian steroid cell tumor was made. Only 4 cases with this association have been reported to date. Of the previously described cases, only one concerns a child; the others were all adult women. All of them had a previous diagnosis of VHL syndrome and presented with secondary amenorrhea and/or hirsutism due to testosterone-secreting ovarian steroid cell tumors. Although extremely rare, the association between VHL syndrome and ovarian steroid cell tumor has been reported, and our case suggests there is a link between the 2 entities.
doi: https://doi.org/10.1097/PGP.0000000000000628
- A new role for the spleen: aggravation of the systemic inflammatory response in rats with severe acute pancreatitis
The American journal of pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31430464
Little is known about the role of the spleen in mediating systemic inflammatory responses in severe acute pancreatitis (SAP). Here, we investigated the role played by the spleen in rats after SAP induction. Splenectomy was performed at designated time points after SAP induction. Pancreatic tissue and serum samples were collected and subjected to histological, immunohistochemical, and immunological analyses. Following SAP induction, the splenic immune response was enhanced during SAP progression, as shown by the increased diameter of the splenic periarterial lymphatic sheath and the thickness of the splenic marginal zone. Rats with splenectomy developed acute pancreatitis more slowly than rats without splenectomy. Additionally, pancreatic tissues of rats with splenectomy contained lower levels of serum amylase, tumor necrosis factor-α, and interleukin-6 and exhibited less acinar cell death, leucocyte infiltration, and interstitial oedema than those of rats without splenectomy. Compared with splenectomy alone, cotreatment with splenectomy and the administration of splenic cells originating from a rat with SAP 12 h after induction increased systemic inflammation in SAP rats. Splenic factors exacerbated SAP-associated liver and lung injury and accentuated intestinal mucosal barrier dysfunction. Splenectomy altered the serum cytokine profile in rats with SAP. In a rat model of SAP, the spleen exacerbated the systematic inflammatory responses and injury to multiple organs, indicating a new role for the spleen in SAP.
doi: https://doi.org/10.1016/j.ajpath.2019.07.008
- ASO Author Reflections: Resection for Metastasis to the Pancreas-Worthwhile for Selected Patients
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31429018
doi: https://doi.org/10.1245/s10434-019-07621-3
- AZD1775 plus chemoradiotherapy for pancreatic cancer
The Lancet. Oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31427207
doi: https://doi.org/10.1016/S1470-2045(19)30537-6
- Significance of Examined Lymph Node Number in Accurate Staging and Long-term Survival in Resected Stage I-II Pancreatic Cancer-More is Better? A Large International Population-based Cohort Study
Annals of surgery 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425290
OBJECTIVE: This large international cohort study aimed to investigate the associations of examined lymph node (ELN) number with accurate staging and long-term survival in pancreatic adenocarcinoma (PaC) and to robustly determine the minimal and optimal ELN thresholds. SUMMARY BACKGROUND DATA: ELN number is an important quality metric in cancer care. The recommended minimal ELN number in PaC to accurately stage cancer varies greatly across guidelines, and the optimal number especially to adequately stratify patient survival has not yet been established. METHODS: Population-based data on patients with stage I to II PaC resected in 2003 to 2015 from the US Surveillance, Epidemiology, and End Results (SEER)-18 Program and Netherlands National Cancer Registry (NCR) were analyzed. Associations of ELN number with stage migration and survival were evaluated using multivariable-adjusted logistic and Cox regression models, respectively. The series of odds ratios (ORs) for negative-to-positive node stage migration and hazard ratios (HRs) for survival with more ELNs were fitted using a LOWESS smoother, and structural breakpoints were determined by Chow test. RESULTS: Overall 16,241 patients were analyzed. With increasing ELN number, both cohorts exhibited significant proportional increases from node-negative to node-positive disease [ORSEER-18=1.05, 95% confidence interval (CI) = 1.04-1.05; ORNCR = 1.10, 95% CI = 1.08-1.12] and serial improvements in survival (HRSEER-18 = 0.98, 95% CI = 0.98-0.99; HRNCR = 0.98, 95% CI = 0.97-0.99) per additional ELN after controlling for confounders. Associations for stage migration and survival remained significant in most stratifications by patient, tumor, and treatment factors. Cut-point analyses suggested a minimal threshold ELN number of 11 and an optimal number of 19, which were validated both internally in the derivative US cohort and externally in the Dutch cohort with the ability to well discriminate different probabilities of both survival and stage migration. CONCLUSIONS: In stage I to II PaC, more ELNs are associated with more precise nodal staging, which might largely explain the survival association. Our observational study does not suggest causality, and does not encourage more extended lymphadenectomy before further randomized evidence is obtained. Our results robustly conclude 11 ELNs as the minimal and suggest 19 ELNs as the optimal cut-points, for evaluating quality of lymph node examination and possibly for stratifying postoperative prognosis.
doi: https://doi.org/10.1097/SLA.0000000000003558
- Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials
The lancet. Diabetes & endocrinology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31422062
BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations, with inconsistent effects on cardiovascular outcomes reported. We aimed to synthesise the available evidence by doing a systematic review and meta-analysis of cardiovascular outcome trials of these drugs. METHODS: We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for eligible placebo-controlled trials reporting major adverse cardiovascular events (MACE; ie, cardiovascular death, stroke, or myocardial infarction) up to June 15, 2019. We did a meta-analysis using a random-effects model to estimate overall hazard ratios (HRs) for MACE, its components, death from any cause, hospital admission for heart failure, kidney outcomes, and key safety outcomes (severe hypoglycaemia, pancreatitis, and pancreatic cancer). We also examined MACE in several subgroups based on patient characteristics (history of cardiovascular disease, BMI, age, baseline HbA1c, and baseline estimated glomerular filtration rate), trial duration, treatment dosing interval, and structural homology. FINDINGS: Of 27 publications screened, seven trials, with a combined total of 56 004 participants, were included: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide). Overall, GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0·88, 95% CI 0·82-0·94; p<0·0001). There was no statistically significant heterogeneity across the subgroups examined. HRs were 0·88 (95% CI 0·81-0·96; p=0·003) for death from cardiovascular causes, 0·84 (0·76-0·93; p<0·0001) for fatal or non-fatal stroke, and 0·91 (0·84-1·00; p=0·043) for fatal or non-fatal myocardial infarction. GLP-1 receptor agonist treatment reduced all-cause mortality by 12% (0·88, 0·83-0·95; p=0·001), hospital admission for heart failure by 9% (0·91, 0·83-0·99; p=0·028), and a broad composite kidney outcome (development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate [or increase in creatinine], progression to end-stage kidney disease, or death attributable to kidney causes) by 17% (0·83, 0·78-0·89; p<0·0001), mainly due to a reduction in urinary albumin excretion. There was no increase in risk of severe hypoglycaemia, pancreatitis, or pancreatic cancer. INTERPRETATION: Treatment with GLP-1 receptor agonists has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes. FUNDING: None.
doi: https://doi.org/10.1016/S2213-8587(19)30249-9
- Long-term outcomes of therapeutic ERCP in pediatric patients with pancreas divisum presenting with acute recurrent or chronic pancreatitis
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31421974
OBJECTIVES: The aim of this study was to evaluate the long-term outcomes of therapeutic endoscopic retrograde cholangiopancreatography (ERCP) for pediatric patients with pancreas divisum (PD) presenting with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). METHODS: Between May 2008 and August 2017, pediatric patients with PD who received endotherapy at Ruijin Hospital were identified and grouped according to clinical presentation, namely ARP and CP. Primary success was defined as patients’ improvement in symptoms after index ERCPs, without further intervention or any analgesic. RESULTS: A total of 74 ERCPs were performed in 38 pediatric patients. The frequency of at least 1 genetic mutation identified in patients with ARP and CP was 44.4% and 68.4%, respectively. Patients with CP required more ERCPs than those with ARP (2.4 ± 1.7 vs. 1.1 ± 0.4, P = 0.005). The incidence of post-ERCP complications was 14.9%, including pancreatitis of 13.5% and hemorrhage of 1.4%. During a median follow-up duration of 41 months (range, 12-123 months), the frequency of pancreatitis episodes decreased significantly from 2.31 to 0.45 (P < 0.0001). The 25% recurrence and reintervention rates were estimated at 25 and 48 months, respectively, without significant difference between patients with ARP or CP. There was a nonsignificant trend towards a higher rate of primary success in patients with ARP than those with CP (92.9% vs. 69.6%, P = 0.123). After further endotherapy, 91.3% patients with CP improved clinically. CONCLUSIONS: Therapeutic ERCP is an effective and safe intervention for pediatric patients with symptomatic PD. Patients presenting with CP seem to achieve improvement after additional ERCPs.
doi: https://doi.org/10.1016/j.pan.2019.08.004
- First-in-human Study of Mivebresib (ABBV-075), an Oral Pan-inhibitor of Bromodomain and Extra Terminal Proteins, in Patients with Relapsed/Refractory Solid Tumors
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31420359
PURPOSE: Bromodomain and extra-terminal (BET) proteins play important roles in transcriptional regulation relevant to cancer pathogenesis, and therapeutic targeting/inhibition of BET causes apoptosis of cancer cells in vitro In this first-in-human study of the pan-BET inhibitor mivebresib (ABBV-075) the safety profile, maximal tolerated dose (MTD), and recommended phase 2 dose (RP2D) were determined in patients with advanced solid tumors. EXPERIMENTAL DESIGN: A 3+3 dose escalation for different mivebresib dosing schedules (daily, Monday/Wednesday/Friday [M-W-F], 4 days on/3 off [4/7]) was followed by dose expansion in prostate cancer patients. Endpoints were safety, tolerability, pharmacokinetics, and preliminary antitumor activity. RESULTS: Seventy-two patients with solid tumors [14% uveal melanoma; 11% colorectal, 11% breast; 8% pancreatic; 7% head/neck; 49% others] were treated with mivebresib during dose escalation, and 12 additional patients with prostate cancer in expansion cohort. Most common TEAEs related to mivebresib were dysgeusia (49%), thrombocytopenia (48%), fatigue (26%) and nausea (25%). Most common grade 3/4 TEAEs related to mivebresib were thrombocytopenia (35%) and anemia (6%). Dose-limiting toxicities included thrombocytopenia (2mg daily; 4.5mg M-W-F), gastrointestinal bleed (2mg daily), hypertension (2-3mg 4/7), fatigue, decreased appetite, and aspartate aminotransferase elevation (4mg M-W-F). Of 61 evaluable patients from dose-escalation, 26 (43%) had stable disease and 35 (57%) had progressive disease. Median progression-free survival was 1.8 months (95%CI: 1.8,1.9). CONCLUSIONS: Based on safety and tolerability, mivebresib RP2D is 1.5mg for the daily schedule, 2.5mg for 4/7 and 3mg for M-W-F. Mivebresib has a tolerable safety profile and stable disease was observed in some patients with malignant solid tumors.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0578
- Pancreatic tumor in type 1 autoimmune pancreatitis: a diagnostic challenge
BMC cancer 2019 Aug;19(1):814
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31419961
BACKGROUND: The co-occurrence of type 1 autoimmune pancreatitis (AIP) and pancreatic tumor (PaT) has been previously reported. Pure AIP cases have favorable prognosis and are primarily treated with steroids, while AIP cases with PaT are associated with poor prognosis where the primary management is pancreatic resection. However, it’s a challenge to timely identify the concurrent PaT in AIP because of their similar clinical and radiological manifestations. METHODS: We retrospectively reviewed the data in two medical centers from January 2010 to April 2019. The inclusion criteria were as follows: 1) completion of abdominal CT imaging before invasive procedures to the pancreas, 2) a final diagnosis of type 1 AIP using the 2011 international consensus diagnostic criteria, 3) follow-up duration of at least one month unless AIP and PaT were identified simultaneously. The presence of PaT in AIP was made based on histopathological confirmation, and the absence of PaT in AIP was defined as no pathological or radiological evidence of concurrent PaT. Clinical and radiological characteristics including gender, age, surveillance period, serum IgG4 and Ca-199 levels, biopsy, extrapancreatic involvement, CT and MR (if performed) imaging characteristics were compared between AIP with and without PaT. The Fisher’s exact test was used for qualitative variables, and nonparametric Mann-Whitney test for quantitative variables. A p value ≤0.05 was considered statistically significant. RESULTS: A total of 74 patients with type 1 AIP were included, of which 5 (6.7%) had the concurrent PaT. The subtypes were pancreatic ductal adenocarcinoma (3/5), solitary extramedullary plasmacytoma in the pancreas (1/5) and cholangiocarcinoma in the pancreatic segment (1/5), respectively. Gender (p = 0.044), the pattern of pancreatic enlargement (p = 0.003), heterogeneity (p = 0.015), low-density (p = 0.004) on CT and rim enhancement on MRI (p = 0.050) differed significantly between AIP with and without PaT. None of the low-density characteristics on CT or other assessed MRI characteristics could significantly differentiate the two groups (p>0.05). CONCLUSIONS: Female, focal pancreatic enlargement, pancreatic heterogeneity, low-density on CT and rim enhancement on MRI are suggestive of the concurrent PaT in type 1 AIP. The characteristics of low-density on CT or other MRI characteristics did not provide further diagnostic values.
doi: https://doi.org/10.1186/s12885-019-6027-0
- Transgenic Expression of PRSS1R122H Sensitizes Mice to Pancreatitis
Gastroenterology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31419436
BACKGROUND & AIMS: Mutations in the trypsinogen gene (PRSS1) cause human hereditary pancreatitis. However, it is not clear how mutant forms of PRSS1 contribute to disease development. We studied the effects of expressing mutant forms of human PRSS1 in mice. METHODS: We expressed forms of PRSS1 with and without the mutation encoding R122H (PRSS1R122H) specifically in pancreatic acinar cells under control of a full-length pancreatic elastase gene promoter. Mice that did not express these transgenes were used as controls. Mice were given injections of caerulein to induce acute pancreatitis or injections of lipopolysaccharide (LPS) to induce chronic pancreatitis. Other groups of mice were fed ethanol or placed on a high-fat diet to induce pancreatitis. Pancreata were collected and analyzed by histology, immunoblots, real-time PCR, and immunohistochemistry. Trypsin enzymatic activity and chymotrypsin enzymatic activity were measured in pancreatic homogenates. Blood was collected and serum amylase activity was measured. RESULTS: Pancreata from mice expressing transgenes encoding PRSS1 or PRSS1R122H had focal areas of inflammation; these lesions were more prominent in mice that express PRSS1R122H. Pancreata from mice that express PRSS1 or PRSS1R122H had increased levels of HSP70 and NRF2 and reduced levels of chymotrypsin C (CTRC), compared with control mice. Increased expression of PRSS1 or PRSS1R122H increased focal damage in pancreatic tissues and increased the severity of acute pancreatitis after caerulein injection. Administration of LPS exacerbated inflammation in mice that express PRSS1R122H compared to mice that express PRSS1 or control mice. Mice that express PRSS1R122H developed more severe pancreatitis after ethanol feeding or a high-fat diet than mice that express PRSS1 or control mice. Pancreata from mice that express PRSS1R122H had more DNA damage, apoptosis, and collagen deposition and increased trypsin activity and infiltration by inflammatory cells than mice that express PRSS1 or control mice. CONCLUSIONS: Expression of a transgene encoding PRSS1R122H in mice promoted inflammation and increase the severity of pancreatitis, compared with mice that express PRSS1 or control mice. These mice might be used as a model for human hereditary pancreatitis and can be studied to determine mechanisms of induction of pancreatitis by LPS, ethanol, or a high-fat diet.
doi: https://doi.org/10.1053/j.gastro.2019.08.016
- Perioperative Gemcitabine + Erlotinib Plus Pancreaticoduodenectomy for Resectable Pancreatic Adenocarcinoma: ACOSOG Z5041 (Alliance) Phase II Trial
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31418130
BACKGROUND: There is considerable interest in a neoadjuvant approach for resectable pancreatic ductal adenocarcinoma (PDAC). This study evaluated perioperative gemcitabine + erlotinib (G+E) for resectable PDAC. METHODS: A multicenter, cooperative group, single-arm, phase II trial was conducted between April 2009 and November 2013 (ACOSOG Z5041). Patients with biopsy-confirmed PDAC in the pancreatic head without evidence of involvement of major mesenteric vessels (resectable) were eligible. Patients (n = 123) received an 8-week cycle of G+E before and after surgery. The primary endpoint was 2-year overall survival (OS), and secondary endpoints included toxicity, response, resection rate, and time to progression. Resectability was assessed retrospectively by central review. The study closed early due to slow accrual, and no formal hypothesis testing was performed. RESULTS: Overall, 114 patients were eligible, consented, and initiated protocol treatment. By central radiologic review, 97 (85%) of the 114 patients met the protocol-defined resectability criteria. Grade 3+ toxicity was reported in 60% and 79% of patients during the neoadjuvant phase and overall, respectively. Twenty-two of 114 (19%) patients did not proceed to surgery; 83 patients (73%) were successfully resected. R0 and R1 margins were obtained in 67 (81%) and 16 (19%) resected patients, respectively, and 54 patients completed postoperative G+E (65%). The 2-year OS rate for the entire cohort (n = 114) was 40% (95% confidence interval [CI] 31-50), with a median OS of 21.3 months (95% CI 17.2-25.9). The 2-year OS rate for resected patients (n = 83) was 52% (95% CI 41-63), with a median OS of 25.4 months (95% CI 21.8-29.6). CONCLUSIONS: For resectable PDAC, perioperative G+E is feasible. Further evaluation of neoadjuvant strategies in resectable PDAC is warranted with more active systemic regimens.
doi: https://doi.org/10.1245/s10434-019-07685-1
- Cell phenotypic plasticity requires autophagic flux driven by YAP/TAZ mechanotransduction
Proceedings of the National Academy of Sciences of the United States of America 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31416916
Autophagy, besides ensuring energy metabolism and organelle renewal, is crucial for the biology of adult normal and cancer stem cells. However, it remains incompletely understood how autophagy connects to stemness factors and the nature of the microenvironmental signals that pattern autophagy in different cell types. Here we advance in these directions by reporting that YAP/TAZ transcriptionally control autophagy, being critical for autophagosomal degradation into autolysosomes. YAP/TAZ are downstream effectors of cellular mechanotransduction and indeed we found that cell mechanics, dictated by the physical property of the ECM and cytoskeletal tension, profoundly impact on autophagic flux in a YAP/TAZ-mediated manner. Functionally, by using pancreatic and mammary organoid cultures, we found that YAP/TAZ-regulated autophagy is essential in normal cells for YAP/TAZ-mediated dedifferentiation and acquisition of self-renewing properties. In tumor cells, the YAP/TAZ-autophagy connection is key to sustain transformed traits and for acquisition of a cancer stem cell state by otherwise more benign cells. Mechanistically, YAP/TAZ promote autophagic flux by directly promoting the expression of Armus, a RAB7-GAP required for autophagosome turnover and whose add-back rescues autophagy in YAP/TAZ-depleted cells. These findings expand the influence of YAP/TAZ mechanotransduction to the control of autophagy and, vice versa, the role of autophagy in YAP/TAZ biology, and suggest a mechanism to coordinate transcriptional rewiring with cytoplasmic restructuring during cell reprogramming.
doi: https://doi.org/10.1073/pnas.1908228116
- A multicenter, open-label, single-arm study of anamorelin (ONO-7643) in advanced gastrointestinal cancer patients with cancer cachexia
Cancer 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31415709
BACKGROUND: Cancer cachexia is characterized by weight loss and is associated with increased morbidity and mortality in patients with cancer. Anamorelin (ONO-7643; ANAM) is a novel and selective ghrelin receptor agonist that improves appetite, lean body mass (LBM), body weight, and anorexia. METHODS: This multicenter, open-label, single-arm study investigated the efficacy and safety of 100 mg anamorelin in 50 Japanese patients with advanced and unresectable gastrointestinal (colorectal, gastric, or pancreatic) cancer. ANAM was administered once daily over 12 weeks. The primary endpoint was the proportion of patients that maintained or gained LBM over the course of the study. Secondary endpoints included changes in LBM, body weight, quality of life (QoL), and nutritional status biomarkers. RESULTS: The proportion of patients who responded to treatment was 63.3% (95% CI, 48.3%-76.6%), with a least square mean ± SE change in LBM and body weight from baseline of 1.89 ± 0.36 kg and 1.41 ± 0.61 kg, respectively. Appetite-related questions on the QoL questionnaire showed that ANAM improved appetite. Adverse events occurred in 79.6% of patients, and the most common treatment-related adverse events were increased γ-glutamyl transpeptidase (8.2%), diabetes mellitus (6.1%), hyperglycemia (6.1%), and prolonged QRS complex (6.1%). CONCLUSIONS: ANAM improved anorexia and patients’ nutritional status, resulting in rapid increases in LBM and body weight in patients with advanced gastrointestinal cancer who had cancer cachexia. ANAM treatment was well tolerated over 12 weeks. ANAM is a potential clinically beneficial pharmacotherapeutic option for patients with advanced gastrointestinal cancer who have cancer cachexia.
doi: https://doi.org/10.1002/cncr.32406
- Grading Pancreatic Neuroendocrine Tumors by Ki-67 Index Evaluated on Fine-Needle Aspiration Cell Block Material
American journal of clinical pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31415691
OBJECTIVES: This study aimed to determine whether Ki-67 index evaluated on cytologic material could reliably grade pancreatic neuroendocrine tumors (PanNETs). METHODS: Cases with adequate cell block and available surgical specimens were included. Ki-67 index was calculated using “eyeballing,” “hot spot,” and “complete” counting methods. RESULTS: The overall concordance rates between cytology and surgical specimens were 71%, 73%, and 59%, respectively, by using eyeballing, hot spot, and complete counting approaches. All grade 1 tumors were correctly graded on cytology, but in grade 2 tumors concordance rates were only 36%, 41%, and 9%, respectively. All grade 2 tumors were undergraded when cell blocks contained fewer than 1,000 cells, while concordance rate increased to 57%, 64%, and 14%, respectively, in cases with 1,000 cells or more. CONCLUSIONS: Grade 2 PanNETs can be significantly undergraded when Ki-67 index is evaluated on cell block material. In cases with 1,000 or more cells, the hot spot counting method has better correlation with surgical specimens.
doi: https://doi.org/10.1093/ajcp/aqz110
- Randomized Comparison of Gastric Tube Reconstruction With and Without Duodenal Diversion Plus Roux-en-Y Anastomosis After Esophagectomy
Annals of surgery 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31415003
OBJECTIVE: This prospective randomized phase-II trial examined whether gastric reconstruction with duodenal diversion plus Roux-en-Y anastomosis(RY) minimized gastroduodenal reflux and delayed gastric emptying compared with standard gastric reconstruction. SUMMARY BACKGROUND DATA: There is no established standard surgical procedure to prevent both gastroduodenal reflux and delayed gastric emptying simultaneously. METHODS: Sixty patients with thoracic esophageal cancer scheduled to undergo esophagectomy with retrosternal gastric tube reconstruction were randomly allocated to standard gastric reconstruction (non-RY, n = 31) or gastric reconstruction with duodenal diversion plus RY (n = 29) groups. Primary endpoint was quality of life assessed by DAUGS-32 score 1 year after surgery. Secondary endpoints were the extent of postoperative duodenal juice reflux into the gastric tube, postoperative morbidity, endoscopic findings, body weight changes, and nutritional status. RESULTS: Preoperative clinicopathological characteristics and postoperative morbidity did not differ significantly between groups. However, operation time and blood loss volume were significantly higher in the RY group. Pancreatic amylase concentrations in the gastric conduit on postoperative days 2, 3, and 7 were higher in the non-RY group. Postoperative endoscopic examination showed residual gastric content in 7 of 17 patients in the non-RY group but in none in the RY group (P = 0.012). Quality of life was significantly favorable in the RY group with regard to reflux symptoms and food passage dysfunction. Postoperative body weight changes, serum albumin levels, and peripheral blood lymphocyte counts were not significantly different between groups. CONCLUSION: Gastric reconstruction with duodenal diversion plus RY is effective in improving both gastroduodenal reflux and delayed gastric emptying.
doi: https://doi.org/10.1097/SLA.0000000000003557
- Rosai-Dorfman Disease of the Digestive System-Beware Vasculopathy: A Clinicopathologic Analysis
The American journal of surgical pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31414989
Rosai-Dorfman disease (RDD) is a rare non-Langerhans cell histiocytic proliferation that occurs in nodal and extranodal sites. Rare examples of the disease involving the digestive system have been described. To characterize the digestive tract manifestations of this disease, 12 specimens from 11 patients with extranodal RDD affecting the digestive organs were analyzed. Hematoxylin and eosin sections and available immunohistochemical stains were reviewed, and the clinical information was obtained from patients’ electronic or submitted records. Eight patients were female and 3 male (median age, 65 y; range, 17 to 76 y). Abdominal pain was the most frequent symptom. Six patients had an associated immunologic or malignant disease. Nine lesions arose in the gastrointestinal tract (1 involving the appendix, 2 right colon, 6 left colon), 2 in the pancreas, and 1 in the liver. Two patients had the coexistent nodal disease, and 1 had bone and soft-tissue involvement. The lesions were generally composed of polygonal to spindle-shaped histiocytes with eosinophilic to clear cytoplasm admixed with lymphoplasmacytic cells. The inflammatory cells formed lymphoid aggregates in 7 cases and included focally scattered or small collections of neutrophils in 6 cases. Fibrosis was variable, and 4 cases had a storiform pattern. Vasculopathy in the form of a thickened capillary wall, medium-sized arterial wall infiltration by lesional and inflammatory cells and phlebitis was seen in 10, 5, and 2 cases, respectively. All cases were reactive for S100-protein. Of the 5 patients with follow-up, 1 developed immunoglobulin A nephropathy and died of renal failure.
doi: https://doi.org/10.1097/PAS.0000000000001343
- The applications of metabolomics in the molecular diagnostics of cancer
Expert review of molecular diagnostics 2019 Aug;():1-9
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31414918
Introduction: Metabolomics, the study of metabolites, is a promising research field for cancers. The metabolic pathway in a tumor cell is different from a normal tissue cell. There are two approaches to study the metabolism, targeted and untargeted. The general approach is that metabolomic data are interpreted by bioinformatics tools correlating with metabolomic databases to obtain significant findings. With the use of specific analysis tools, such as nuclear magnetic resonance (NMR) and mass spectrometer (MS) combined with chromatography, metabolic profile or metabolic fingerprint of various biological specimens could be obtained. The applications of metabolomics are used to discover potential cancer biomarkers and monitor the metastatic state, therapeutic and drug response for better patient management. Areas covered: In this review, the author introduce metabolomics and discuss the use of metabolomics approaches in different cancers, including the study of colorectal cancer, prostate cancer, liver cancer, pancreatic cancer and breast cancer using NMR and MS. Expert opinion: Knowledge on the molecular basis of cancer metabolism and its potential clinical applications has been improving recently. However, there are still many challenges for the technological development and integration of metabolomics with other omics spaces such as genomics. In the near future, it is expected that metabolomics will play an important role in cancer molecular diagnostics.
doi: https://doi.org/10.1080/14737159.2019.1656530
- Lipid droplet velocity is a microenvironmental sensor of aggressive tumors regulated by V-ATPase and PEDF
Laboratory investigation; a journal of technical methods and pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31409893
Lipid droplets (LDs) utilize microtubules (MTs) to participate in intracellular trafficking of cargo proteins. Cancer cells accumulate LDs and acidify their tumor microenvironment (TME) by increasing the proton pump V-ATPase. However, it is not known whether these two metabolic changes are mechanistically related or influence LD movement. We postulated that LD density and velocity are progressively increased with tumor aggressiveness and are dependent on V-ATPase and the lipolysis regulator pigment epithelium-derived factor (PEDF). LD density was assessed in human prostate cancer (PCa) specimens across Gleason scores (GS) 6-8. LD distribution and velocity were analyzed in low and highly aggressive tumors using live-cell imaging and in cells exposed to low pH and/or treated with V-ATPase inhibitors. The MT network was disrupted and analyzed by α-tubulin staining. LD density positively correlated with advancing GS in human tumors. Acidification promoted peripheral localization and clustering of LDs. Highly aggressive prostate, breast, and pancreatic cell lines had significantly higher maximum LD velocity (LDVmax) than less aggressive and benign cells. LDVmax was MT-dependent and suppressed by blocking V-ATPase directly or indirectly with PEDF. Upon lowering pH, LDs moved to the cell periphery and carried metalloproteinases. These results suggest that acidification of the TME can alter intracellular LD movement and augment velocity in cancer. Restoration of PEDF or blockade of V-ATPase can normalize LD distribution and decrease velocity. This study identifies V-ATPase and PEDF as new modulators of LD trafficking in the cancer microenvironment.
doi: https://doi.org/10.1038/s41374-019-0296-8
- Mouse pancreatic ductal organoid culture as a relevant model to study exocrine pancreatic ion secretion
Laboratory investigation; a journal of technical methods and pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31409889
Pancreatic exocrine secretory processes are challenging to investigate on primary epithelial cells. Pancreatic organoid cultures may help to overcome shortcomings of the current models, however the ion secretory processes in pancreatic organoids-and therefore their physiological relevance or their utility in disease modeling-are not known. To answer these questions, we provide side-by-side comparison of gene expression, morphology, and function of epithelial cells in primary isolated pancreatic ducts and organoids. We used mouse pancreatic ductal fragments for experiments or were grown in Matrigel to obtain organoid cultures. Using PCR analysis we showed that gene expression of ion channels and transporters remarkably overlap in primary ductal cells and organoids. Morphological analysis with scanning electron microscopy revealed that pancreatic organoids form polarized monolayers with brush border on the apical membrane. Whereas the expression and localization of key proteins involved in ductal secretion (cystic fibrosis transmembrane conductance regulator, Na+/H+ exchanger 1 and electrogenic Na+/HCO3- cotransporter 1) are equivalent to the primary ductal fragments. Measurements of intracellular pH and Cl- levels revealed no significant difference in the activities of the apical Cl-/HCO3- exchange, or in the basolateral Na+ dependent HCO3- uptake. In summary we found that ion transport activities in the mouse pancreatic organoids are remarkably similar to those observed in freshly isolated primary ductal fragments. These results suggest that organoids can be suitable and robust model to study pancreatic ductal epithelial ion transport in health and diseases and facilitate drug development for secretory pancreatic disorders like cystic fibrosis, or chronic pancreatitis.
doi: https://doi.org/10.1038/s41374-019-0300-3
- Prognostic significance of neutrophil-lymphocyte ratio in resectable pancreatic neuroendocrine tumors with special reference to tumor-associated macrophages
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31409525
BACKGROUND: Recent studies have shown that the systemic inflammatory response induced by cancer leads to cancer progression. Neutrophil-to-lymphocyte ratio (NLR) is the most reliable marker to detect systemic inflammation. In this study, we investigated the significance of NLR in patients with well-differentiated pancreatic neuroendocrine tumors (PanNETs) according to the World Health Organization 2017 classification. METHODS: We retrospectively collected data for patients with PanNET who underwent pancreatic resection with curative intent between January 2008 and December 2017 at six institutions. Clinicopathological factors, recurrence, and immunohistochemical staining of tumor-associated macrophages (TAMs) were analyzed in a total of 55 patients in this study. RESULTS: High NLR (>3.41) in patients was significantly associated with higher white blood cell count, higher Ki-67 index, higher mitotic count, higher grade, higher incidence of lymph node metastasis, higher incidence of lymphatic and neural invasion, massive blood loss, and a large number of CD163-expressing TAMs. Recurrence-free survival of patients with high NLR was significantly poorer than that of patients with low NLR. Multivariate analysis identified high NLR, NET Grade 2 (G2) or Grade 3 (G3), and synchronous hepatic resection as independent risk factors for recurrence after curative resection. CONCLUSIONS: NLR is a promising predictor of recurrence after pancreatectomy that needs to be further investigated and that accumulation of TAMs in the tumor could be one of the causes of NLR elevation.
doi: https://doi.org/10.1016/j.pan.2019.08.003
- Dissecting the presence of malignant squamous cells in pancreatic cytopathology: A case series
Diagnostic cytopathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31407529
The presence of malignant squamous cells in pancreatic cytopathology is a rare phenomenon that results either from a primary or a metastatic process. Pancreatic adenosquamous carcinoma (PASC) represents the most common variant of pancreatic ductal adenocarcinoma and is associated with a dismal prognosis. Within the period of 2013-2018, the archives of “Hygeia and Mitera Hospital” were searched for pancreatic cytopathology-related diagnoses that included the interpretation of “malignant squamous cells present.” All fine needle aspirations (FNAs) of pancreatic lesions, including liver metastases in patients with known pancreatic primaries, were retrieved along with their relevant clinical information. Five pancreatic and two liver FNAs acquired from a total of six patients were reexamined. None of these patients had any documented history of primary squamous malignancy elsewhere. All pancreatic and one of the two liver FNAs showed malignant squamous cells, identified based on either morphology or immunochemistry. The other liver FNA represented a metastatic deposit which comprised of only a glandular component, whereas the associated pancreatic FNA exhibited both squamous and glandular counterparts. Most cases characteristically showed necrosis and keratinization. Of interest, two cases revealed the presence of tumor-associated giant cells. In conclusion, the presence of malignant squamous cells in pancreatic FNAs could mean the presence of PASC, especially when there is no documented history of a primary malignancy and a complete clinical and imaging workup has been performed. Immunochemistry on cell block material could help to confirm squamous differentiation in the absence of overt keratinization.
doi: https://doi.org/10.1002/dc.24302
- Laparoscopic Suprapancreatic Lymph Node Dissection Using a Systematic Mesogastric Excision Concept for Gastric Cancer
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31407184
BACKGROUND: Gastrointestinal cancer surgery requires en bloc removal of the primary tumor and organ-specific mesentery1,2. However, this surgical concept for gastric cancer has not yet been applied because of the morphological complexity of the mesenteries of the stomach. Lymph node dissection in gastric cancer surgery can be roughly performed into three regions: lesser curvature, grater curvature, and suprapancreatic region. In this video, we introduced laparoscopic lymphadenectomy in the suprapancreatic region using a systematic mesogastric excision (SME), which has been reported as a concept to perform en bloc resection3. METHODS: This procedure was divided into three steps. First, mesenterization of the mesogastrium was performed by dissecting the embryological planes, and the mesogastrium was dissected from the retroperitoneal surface (Fig. 1a). Second, soft tissue, including the lymph node, was separated from the pancreas and the splenic artery by tracing the inner dissectable layer (Fig. 1b). Finally, the tumor-specific mesentery was transected according to the extent of the lymphadenectomy (Fig. 1c). Fig. 1 Intraoperative findings during the stepwise procedure in dissecting the lymph node in the suprapancreatic region. The red broken line indicates the surgical outline. a The mesogastrium is dissected from the retroperitoneal tissue. b The mesogastrium is separated from the pancreas and splenic artery. c The mesogastric transection line is determined on the basis of the extent of the lymphadenectomy. Inf. phrenic a. inferior phrenic artery; PGA posterior gastric artery; Post. epiploic a. posterior epiploic artery; RV renal vein; SA splenic artery; SV splenic vein RESULTS: Between January 2017 and December 2017, six patients underwent laparoscopic distal gastrectomy with D2 lymphadenectomy using SME. The median time required to complete the suprapancreatic lymphadenectomy was 48 min. No patient underwent conversion to open surgery or experienced intraoperative complications. CONCLUSIONS: We believe that this laparoscopic suprapancreatic lymphadenectomy using SME takes advantage of the surgical anatomy and achieves en bloc removal of the primary tumor and gastric mesentery. This series is a proof of concept that this procedure can be performed in a timely manner and is feasible.
doi: https://doi.org/10.1245/s10434-019-07700-5
- Extended Laparoscopic Central Pancreatectomy with Clamping of the Mesentericoportal Vein and Resection of the Splenic Vessels for a Large Solid Pseudopapillary Tumor
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31407182
BACKGROUND: Solid pseudopapillary tumors (SPPTs) are low malignant potential entities found mainly in young females.1,2 Pancreatectomy without tumor rupture is the treatment of choice, and the laparoscopic approach is indicated.3,4 Limited pancreatectomy is possible due to the low risk of malignancy (< 10%) based on the low risk of lymph node invasion or true vascular invasion.1,2 Centrally located large SPPTs can be treated by extended central pancreatectomy with or without vascular resection to avoid pancreatoduodenectomy or distal pancreatectomy. METHODS: A 24-year-old woman was admitted with abdominal pain. A 6-cm SPPT was discovered at the neck-body junction in close contact with the anterior aspect of the mesentericoportal vein (MPV) and the splenic vessels, with signs of segmental portal hypertension. To avoid an extended pancreatectomy for this young patient, an extended central pancreatectomy was performed, with resection of the splenic vessels, and the MPV was freed from the tumor under clamping for 10 min, with no need for vascular reconstruction. The duration of the surgery was 260 min, with 200 ml of blood loss and no transfusion. RESULTS: The woman’s postoperative course was uneventful, with a hospital stay of 16 days. Histology confirmed the diagnosis of a 6-cm SPPT tumor (R0 and N0). The patient was asymptomatic 1 year later, with no tumor recurrence and no pancreatic insufficiency. Between 2011 and 2018 the authors performed 72 laparoscopic central pancreatectomies, with SPPT performed for 13 patients (18%). Laparoscopic central pancreatectomy was extended (n = 5) or standard (n = 8) with no conversion, no recurrence, and no pancreatic insufficiency. CONCLUSION: An SPPT tumor is a good indication for the laparoscopic approach because this entity is found in young patients with a low risk of malignancy. Large centrally located tumors can be treated by extended central pancreatectomy to avoid a large pancreatectomy with greater early and long-term disadvantages.
doi: https://doi.org/10.1245/s10434-019-07689-x
- Robotic Extended Right Hemicolectomy with Complete Mesocolic Excision and D3 Lymph Node Dissection
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31407176
BACKGROUND: Recent studies have shown the benefits of complete mesocolic excision and extended lymphadenectomy (D3 lymph node dissection) in patients with colon cancer.1-3 METHODS: We present the case of a 62-year-old male with hepatic flexure adenocarcinoma. No metastatic disease was identified by computed tomography. A robot-assisted extended right hemicolectomy with complete mesocolic excision, D3 lymph node dissection, and resection of the mesentery with intact visceral peritoneum was performed. RESULTS: The trocars are placed in the right lower (8 mm), lower midline (8 mm), and left upper (12 mm) quadrants. The camera port is placed superior to the umbilicus, and the assistant port is placed in the left lower quadrant. The robotic right lower port is used to place the cecum on tension in order to outline the ileocolic pedicle. The assistant retracts the transverse colon cephalad to outline the superior mesenteric artery and vein. Using two robotic arms, the surgeon begins dissection over the superior mesenteric vein inferior to the ileocolic pedicle. Cephalad dissection along the superior mesenteric vein proceeds with reflection of the mesentery and D3 lymph nodes laterally to allow en bloc resection. The ileocolic and middle colic vessels are identified, ligated and divided at their origins. The plane is then developed between the right colon mesentery and the retroperitoneum, including Gerota’s fascia, duodenum, and head of the pancreas, in a medial-to-lateral fashion, with care taken to ensure an intact visceral peritoneum is maintained. The proximal transverse colon, hepatic flexure, and ascending colon are mobilized by taking down lateral attachments. The intervening mesentery is transected, and perfusion is assessed with indocyanine green fluorescence imaging. An intracorporeal, isoperistaltic, side-to-side anastomosis is performed using the 45-mm robotic stapler. The common enterotomy is sewn closed in two layers. Pathology showed T3N0 adenocarcinoma with all negative margins. CONCLUSION: Extended right hemicolectomy with complete mesocolic excision and D3 lymph node dissection is facilitated by a robotic approach, which improves visualization and instrument dexterity.
doi: https://doi.org/10.1245/s10434-019-07692-2
- Short-Term Outcomes of Laparoscopic and Open Total Gastrectomy for Gastric Cancer: A Nationwide Retrospective Cohort Analysis
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31407172
BACKGROUND: Laparoscopic total gastrectomy is gradually gaining popularity; however, previous studies have produced conflicting results regarding the safety and advantages of the procedure, partly because of small sample sizes. The purpose of this study was to compare short-term outcomes between laparoscopic and open total gastrectomy for gastric cancer. METHODS: We analyzed data for patients undergoing laparoscopic or open total gastrectomy for clinical stage I-III gastric cancer from July 2010 to March 2017, using a Japanese nationwide inpatient database. We performed propensity-matched analyses to compare in-hospital mortality, morbidity, duration of anesthesia, time to first oral intake, and length of postoperative stay between the two groups. RESULTS: Among 58,689 eligible patients, propensity-score matching created 12,229 pairs. Laparoscopic total gastrectomy was associated with higher incidences of anastomotic leakage (2.9% vs. 1.7%, p < 0.001) and stenosis (0.9% vs. 0.6%, p = 0.02), lower incidences of pancreatic injury (1.4% vs. 1.8%, p = 0.01), endoscopic hemostasis (0.9% vs. 1.7%, p < 0.001), blood transfusion (9.9% vs. 17.7%, p < 0.001) and 30-day readmission, a shorter interval from surgery to first oral intake (4 vs. 5 days, p < 0.001), shorter postoperative hospital stay (14 vs. 15 days, p < 0.001), and a longer duration of anesthesia (323 vs. 304 min, p < 0.001). There was no significant difference in in-hospital mortality (0.6% vs. 0.8%, p = 0.58). CONCLUSIONS: Laparoscopic total gastrectomy has some advantages over open surgery for gastric cancer in terms of time to first oral intake and postoperative length of stay, but the incidence of anastomotic leakage was higher than that of open total gastrectomy.
doi: https://doi.org/10.1245/s10434-019-07688-y
- Pancreas FNA
Cytopathology : official journal of the British Society for Clinical Cytology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31400170
67-year-old lady diagnosed with right breast invasive ductal carcinoma with axillary node involvement. Staging FDG PET identified a small enhancing 1.2cm ‘indeterminate’ nodule within pancreatic tail, which CT pancreas with contrast revealed to be hypervascular. This article is protected by copyright. All rights reserved.
doi: https://doi.org/10.1111/cyt.12767
- Comparison of Tissue and Blood Concentrations of Oxaliplatin Administrated by Different Modalities of Intraperitoneal Chemotherapy
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31399820
BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new technology for delivering intraperitoneal chemotherapy. It is generally assumed that with PIPAC, the ratio of peritoneal to systemic drug concentration is superior to liquid hyperthermic intraperitoneal chemotherapy (HIPEC). To date, no direct comparative data are available supporting such an assumption. MATERIALS AND METHODS: Twelve 65-day-old pigs were randomly separated into three groups of four pigs each, all of which received intraperitoneal chemotherapy using the following administration methods: PIPAC with oxaliplatin 92 mg in 150 ml dextrose 5% (Group 1); PIPAC with electrostatic aerosol precipitation (ePIPAC; Group 2); or laparoscopic HIPEC (L-HIPEC) with oxaliplatin 400 mg in 4 L dextrose 5% at 42 °C (Group 3). Serial blood and peritoneal tissue concentrations of oxaliplatin were determined by spectrometry. RESULTS: In all three groups, the maximum concentration of oxaliplatin in blood was detected 50-60 min after onset of the chemotherapy experiments, with no significant differences among the three groups (p = 0.7994). Blood oxaliplatin concentrations (0-30 min) were significantly higher in the L-HIPEC group compared with the ePIPAC group (p < 0.05). No difference was found for the overall systemic oxaliplatin absorption (area under the curve). Overall concentrations in the peritoneum were not different among the three groups (p = 0.4725), but were significantly higher in the visceral peritoneum in the PIPAC group (p = 0.0242). CONCLUSIONS: Blood and tissue concentrations were comparable between all groups; however, depending on the intraperitoneal area examined and the time points of drug delivery, the concentrations differed significantly between the three groups.
doi: https://doi.org/10.1245/s10434-019-07695-z
- ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer
Proceedings of the National Academy of Sciences of the United States of America 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31399545
Although KRAS and TP53 mutations are major drivers of pancreatic ductal adenocarcinoma (PDAC), the incurable nature of this cancer still remains largely elusive. ARF6 and its effector AMAP1 are often overexpressed in different cancers and regulate the intracellular dynamics of integrins and E-cadherin, thus promoting tumor invasion and metastasis when ARF6 is activated. Here we show that the ARF6-AMAP1 pathway is a major target by which KRAS and TP53 cooperatively promote malignancy. KRAS was identified to promote eIF4A-dependent ARF6 mRNA translation, which contains a quadruplex structure at its 5’-untranslated region, by inducing TEAD3 and ETV4 to suppress PDCD4; and also eIF4E-dependent AMAP1 mRNA translation, which contains a 5’-terminal oligopyrimidine-like sequence, via up-regulating mTORC1. TP53 facilitated ARF6 activation by platelet-derived growth factor (PDGF), via its known function to promote the expression of PDGF receptor β (PDGFRβ) and enzymes of the mevalonate pathway (MVP). The ARF6-AMAP1 pathway was moreover essential for PDGF-driven recycling of PD-L1, in which KRAS, TP53, eIF4A/4E-dependent translation, mTOR, and MVP were all integral. We moreover demonstrated that the mouse PDAC model KPC cells, bearing KRAS/TP53 mutations, express ARF6 and AMAP1 at high levels and that the ARF6-based pathway is closely associated with immune evasion of KPC cells. Expression of ARF6 pathway components statistically correlated with poor patient outcomes. Thus, the cooperation among eIF4A/4E-dependent mRNA translation and MVP has emerged as a link by which pancreatic driver mutations may promote tumor cell motility, PD-L1 dynamics, and immune evasion, via empowering the ARF6-based pathway and its activation by external ligands.
doi: https://doi.org/10.1073/pnas.1901765116
- Second harmonic generation detection of Ras conformational changes and discovery of a small molecule binder
Proceedings of the National Academy of Sciences of the United States of America 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31399543
Second harmonic generation (SHG) is an emergent biophysical method that sensitively measures real-time conformational change of biomolecules in the presence of biological ligands and small molecules. This study describes the successful implementation of SHG as a primary screening platform to identify fragment ligands to oncogenic Kirsten rat sarcoma (KRas). KRas is the most frequently mutated driver of pancreatic, colon, and lung cancers; however, there are few well-characterized small molecule ligands due to a lack of deep binding pockets. Using SHG, we identified a fragment binder to KRasG12D and used 1H 15N transverse relaxation optimized spectroscopy (TROSY) heteronuclear single-quantum coherence (HSQC) NMR to characterize its binding site as a pocket adjacent to the switch 2 region. The unique sensitivity of SHG furthered our study by revealing distinct conformations induced by our hit fragment compared with 4,6-dichloro-2-methyl-3-aminoethyl-indole (DCAI), a Ras ligand previously described to bind the same pocket. This study highlights SHG as a high-throughput screening platform that reveals structural insights in addition to ligand binding.
doi: https://doi.org/10.1073/pnas.1905516116
- Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes
Cell 2019 Aug;178(4):795-806.e12
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31398337
Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.
doi: https://doi.org/10.1016/j.cell.2019.07.008
- Variation in use of open and laparoscopic distal pancreatectomy and associated outcome metrics in a universal health care system
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31395453
BACKGROUND: Universal health care (UHC) should ensure equal access to and use of surgery, but few studies have explored variation in UHC systems. The objective was to describe practice of distal pancreatectomy in Norway covered exclusively by an UHC. METHODS: Data on all patients undergoing distal pancreatectomy from the Norwegian Patient Register over a 5-year period. Age- and gender-adjusted population-based resection rates (adj. per million/yr) for distal pancreatectomy were analysed across 4 regions and outcomes related to splenic salvage rate, hospital stay, reoperation, readmissions and 90-day mortality risk between regions. Risk is reported as odds ratio (OR) with 95% confidence interval (c.i.). RESULTS: Regional difference exist in terms of absolute numbers, with the majority of procedures done in one region (n = 331; 59.7%). Regional variation persisted for age- and gender-adjusted population-rates, with highest rate at 23.8/million/yr and lowest rate at 13.5/mill/yr (for a 176% relative difference; or an absolute difference of +10.3 resections/million/yr). Overall, a lapDP instead of an open DP was 3.5 times more likely in SouthEast compared to all other regions combined (lapDP rate: 83% vrs 24%, respectively; OR 15.4, 95% c.i. 10.1-23.5; P < 0.001). The splenic salvage rate was lower in SouthEast (19.9%) compared to all other regions (average 26.5%; highest in Central-region at 37.0%; P = 0.010 for trend). Controlled for other factors in multivariate regression, ‘region’ of surgery remained significantly associated with laparoscopic access. CONCLUSION: Despite a universal health care system, considerable variation exists in resection rates, use of laparoscopy and splenic salvage rates across regions.
doi: https://doi.org/10.1016/j.pan.2019.07.047
- Comparison of overall survival and perioperative outcomes of laparoscopic pancreaticoduodenectomy and open pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: a systematic review and meta-analysis
BMC cancer 2019 Aug;19(1):781
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31391085
BACKGROUND: The aim of this study was to compare the oncological outcomes and clinical efficacy of laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD) in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: We systematically searched PubMed, EMBASE, Web of Science, ClinicalTrials.gov and the Cochrane Central Register for studies published between May 1998 and May 2018. The included studies compared LPD and OPD for the treatment of PDAC. The oncological outcomes and perioperative data were analyzed. RESULTS: Eight studies involving 15,278 patients were included in our meta-analysis. No significant difference was found in the 5-year overall survival (OS) between patients undergoing the two types of surgery (HR: 0.97, 95% CI 0.82-1.15, p = 0.76). LPD resulted in a higher rate of R0 resection than OPD (OR: 1.16, 95% CI 0.85-1.57, p > 0.05). This study showed that compared with OPD, LPD resulted in comparable rates of postoperative pancreatic fistulas (POPFs) (OR: 1.07, 95% CI: 0.68-1.68, p = 0.77) and postoperative hemorrhage (OR: 1.74, 95% CI 0.96-3.71, p = 0.07), more harvested lymph nodes (WMD: 1.84, 95% CI: 0.95-2.72, p < 0.05), shorter hospital stays (WMD: -2.45, 95% CI: - 3.33- -1.56, p < 0.05), and less estimated blood loss (WMD: -374.30, 95% CI: - 513.06- -235.54, p < 0.05). CONCLUSIONS: LPD is equivalent to OPD with respect to 5-year OS and results in better perioperative clinical outcomes for patients with PDAC.
doi: https://doi.org/10.1186/s12885-019-6001-x
- A 12-year trend analysis of the incidence of gastrointestinal cancers in East Azerbaijan: last updated results of an ongoing population-based cancer registry
BMC cancer 2019 Aug;19(1):782
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31391032
BACKGROUND: The most recent results of Global Cancer Statistics indicated that gastrointestinal cancers, including gastric, colorectal, esophageal, and liver cancers, are among the most commonly diagnosed cancers worldwide. Previous reports from cancer registries in East Azerbaijan have shown that there is a high incidence of gastrointestinal cancer in this region, so we performed a trend analysis to determine the pattern of change over the last decade. METHODS: In total, 12 years of cancer registry data were collected from different sources in East Azerbaijan, and a data quality check was performed to ensure clean data. Using the 2000 World Health Organization standard population, we then generated age-standardized incidence rates (ASRs) for different cancers, and for each year from 1383 to 1394 of the Persian calendar (i.e., 19 March 2004 to 20 March 2015). Annual percent changes (APCs) and Average annual percent changes (AAPCs) in the ASRs for esophageal, gastric, small intestine, colorectal, anal, liver, gallbladder, and pancreatic cancers were calculated using Joinpoint Software (Version 4.5.0.1, June 2017). RESULTS: An increase in most types of cancer was observed during the study period. The ASR for colorectal cancer increased from 2.9 to 13.6 per 100,000 women (APC, 9.7%) and from 2.2 to 17.8 per 100,000 men (APC, 10.2%). The ASR for gastric cancer showed a slight increasing trend from 10.5 to 13.5 per 100,000 women (APC, 1.3%) and from 3.1 to 29.9 per 100,000 men (APC, 3.2%). However, trend analysis showed a decreasing pattern for the ASR of esophageal cancer in both genders (APC,- 3%), with APCs of - 1.1% in females and - 0.4% in males. CONCLUSIONS: The latest results of the East Azerbaijan Population-Based Cancer Registry indicate that gastrointestinal cancers remain common, with significant increasing trends in their ASRs. Improved screening and early detection are needed in this region.
doi: https://doi.org/10.1186/s12885-019-6008-3
- The prognostic value of lncRNA SNHG1 in cancer patients: a meta-analysis
BMC cancer 2019 Aug;19(1):780
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31391030
BACKGROUND: Increasing evidence revealed that high expression level of lncRNA SNHG1 was associated with the unfavorable prognosis of cancer and maybe used as a valuable biomarker for cancer patients. The present meta->analysis is to analyze existing data to reveal potential clinical application of SNHG1 on cancer prognosis and tumor progression. All of the included studies were collected through a variety of retrieval strategies. And the articles were qualified by MOOSE and PRISMA checklists. METHODS: Up to Mar 20, 2018, literature collection was performed by comprehensive search through electronic databases, including the Cochrane library, PubMed, Embase, Web of science, Springer, Science direct, and three Chinese databases: CNKI, Weipu, and Wanfang. We analyzed 14 studies that met the criteria, and concluded that the increased SHNG1 level was correlated with poor OS and tumor progression. RESULTS: The combined results indicated that elevated SNHG1 expression level was significantly associated with poor OS (HR = 2.06, 95% CI: 1.69-2.52, P < 0.01) and PFS (HR = 2.78, 95% CI: 1.69-4.55, P < 0.01) in various cancers. Moreover, the promoted SNHG1 expression was also associated with tumor progression ((III/IV vs. I/II: HR = 1.89, 95% CI: 1.53-2.34, P < 0.01). In stratified analyses, a significantly unfavorable association of elevated lncRNA SNHG1 and OS was observed in both digestive system (HR = 2.04, 95% CI: 1.56-2.68, P < 0.01) and non-digestive system (HR = 2.09, 95% CI: 1.55-2.83, P < 0.01) cancer patients. CONCLUSIONS: The present analysis indicated that the increased SNHG1 is associated with poor OS in patients with general tumors and may be served as a useful prognostic biomarker.
doi: https://doi.org/10.1186/s12885-019-5987-4
- Dynamic serum alkaline phosphatase is an indicator of overall survival in pancreatic cancer
BMC cancer 2019 Aug;19(1):785
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31391026
BACKGROUND: The prognostic role of serum alkaline phosphatase (ALP) has been found in several kinds of solid malignant tumor, but has never been extensively discussed in pancreatic cancer, especially through the application of dynamic survival model which incorporates the varying nature of ALP measurements. METHODS: We conducted a retrospective study which successfully collected 551 histopathologically confirmed pancreatic ductal adenocarcinoma (PDAC) patients from a cancer specialized hospital in southwest China. The association between variant ALP which measured during the whole survival period and the overall survival (OS) of PDAC patients was evaluated by using dynamic Anderson-Gill (AG) model. Exhaustive sensitivity analysis was performed by adopting continuous cut-offs of ALP. RESULTS: After adjusted for possible confounding of serum albumin, total bilirubin and leukocyte counts, AG model revealed that, serum ALP during the survival period was nonlinearly associated with the OS of PDAC: for resected patients, compared with those whose ALP results ranged within the first quartile (<P25), patients whose ALP measurements belonged to the second (P25-P50), the third (P50-P75), and the forth (>P75) quartiles were observed 1.14 (95% CI: 0.29-4.56), 3.93 (95% CI: 1.23-12.60), 3.87 (95% CI: 1.32-11.36) folds of death hazard; whereas in un-resected PDAC patients, the hazard ratios (HRs) were 1.15 (95% CI: 0.79-1.68), 1.92 (95% CI: 1.32-2.78), and 1.97 (95% CI: 1.30-2.98), respectively. Sensitivity analysis revealed that, for both resected and un-resected patients, the results of AG model were robust with regard to various cut-offs of ALP, and an increased ALP was in general associated with significantly increased hazard of death. CONCLUSION: Serum ALP during the survival period was significantly associated with the OS of PDAC patients, especially for resected early stage PDAC patients. Future studies with expanded sample size and refined prospective design should be implemented to corroborate our major findings. Besides, the underlying mechanism for this possible hazardous role of ALP should also be investigated.
doi: https://doi.org/10.1186/s12885-019-6004-7
- Corrigendum to “Cystic pancreatic neuroendocrine tumors: A more favorable lesion?” [Pancreatology 19 (2) (March 2019) 372-376]
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31387834
doi: https://doi.org/10.1016/j.pan.2019.07.043
- Classification of Complication Clusters Might Vary in Different Populations With Chronic Pancreatitis
The American journal of gastroenterology 2019 Aug;114(8):1351-1352
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31386633
doi: https://doi.org/10.14309/ajg.0000000000000292
- Sclerosing epithelioid mesenchymal neoplasm of the pancreas - a proposed new entity
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31383964
We have encountered pancreatic tumors with unique histologic features, which do not conform to any of the known tumors of the pancreas or other anatomical sites. We aimed to define their clinicopathologic features and whether they are characterized by recurrent molecular signatures. Eight cases were identified; studied histologically and by immunohistochemistry. Selected cases were also subjected to whole-exome sequencing (WES; n = 4), RNA-sequencing (n = 6), Archer FusionPlex assay (n = 5), methylation profiling using the Illumina MethylationEPIC (850k) array platform (n = 6), and TERT promoter sequencing (n = 5). Six neoplasms occurred in females. The mean age was 43 years (range: 26-75). Five occurred in the head/neck of the pancreas. All patients were treated surgically; none received neoadjuvant/adjuvant therapy. All patients are free of disease after 53 months of median follow-up (range: 8-94). The tumors were well-circumscribed, and the median size was 1.8 cm (range: 1.3-5.8). Microscopically, the unencapsulated tumors had a geographic pattern of epithelioid cell nests alternating with spindle cell fascicles. Some areas showed dense fibrosis, in which enmeshed tumor cells imparted a slit-like pattern. The predominant epithelioid cells had scant cytoplasm and round-oval nuclei with open chromatin. The spindle cells displayed irregular, hyperchromatic nuclei. Mitoses were rare. No lymph node metastases were identified. All tumors were positive for vimentin, CD99 and cytokeratin (patchy), while negative for markers of solid pseudopapillary neoplasm, neuroendocrine, acinar, myogenic/rhabdoid, vascular, melanocytic, or lymphoid differentiation, gastrointestinal stromal tumor as well as MUC4. Whole-exome sequencing revealed no recurrent somatic mutations or amplifications/homozygous deletions in any known oncogenes or tumor suppressor genes. RNA-sequencing and the Archer FusionPlex assay did not detect any recurrent likely pathogenic gene fusions. Single sample gene set enrichment analysis revealed that these tumors display a likely mesenchymal transcriptomic program. Unsupervised analysis (t-SNE) of their methylation profiles against a set of different mesenchymal neoplasms demonstrated a distinct methylation pattern. Here, we describe pancreatic neoplasms with unique morphologic/immunophenotypic features and a distinct methylation pattern, along with a lack of abnormalities in any of key genetic drivers, supporting that these neoplasms represent a novel entity with an indolent clinical course. Given their mesenchymal transcriptomic features, we propose the designation of “sclerosing epithelioid mesenchymal neoplasm” of the pancreas.
doi: https://doi.org/10.1038/s41379-019-0334-5
- Pancreatic cancer-A disease in need: Optimizing and integrating supportive care
Cancer 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31381149
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that continues to be challenging to treat. PDAC has the lowest 5-year relative survival rate compared with all other solid tumor malignancies and is expected to become the second-leading cause of cancer-related death in the United States by 2030. Given the high mortality, there is an increasing role for concurrent anticancer and supportive care in the management of patients with PDAC with the aims of maximizing length of life, quality of life, and symptom control. Emerging trends in supportive care that can be integrated into the clinical management of patients with PDAC include standardized supportive care screening, early integration of supportive care into routine cancer care, early implementation of outpatient-based advance care planning, and utilization of electronic patient-reported outcomes for improved symptom management and quality of life. The most common symptoms experienced are nausea, constipation, weight loss, diarrhea, anorexia, and abdominal and back pain. This review article includes current supportive management strategies for these and others. Common disease-related complications include biliary and duodenal obstruction requiring endoscopic procedures and venous thromboembolic events. Patients with PDAC continue to have a poor prognosis. Systemic therapy options are able to palliate the high symptom burden but have a modest impact on overall survival. Early integration of supportive care can lead to improved outcomes.
doi: https://doi.org/10.1002/cncr.32423
- The Impact of Dedicated Cancer Centers on Outcomes Among Medicare Beneficiaries Undergoing Liver and Pancreatic Cancer Surgery
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31376033
BACKGROUND: The Alliance of Dedicated Cancer Centers (DCCs) is comprised of 11 institutions that are exempt from the prospective payment system utilized by Medicare for hospital reimbursement. OBJECTIVE: The aim of this study was to compare short- and long-term outcomes of patients undergoing liver and pancreatic surgery for cancer at DCCs versus non-DCCs. METHODS: Patients who underwent a liver or pancreatic operation for a malignant indication between 2013 and 2015 were identified using the Medicare Inpatient Standard Analytic Files. Regression analyses and the Kaplan-Meier method were used to assess short- and long-term outcomes of patients at DCCs versus non-DCCs. RESULTS: Among 13,256 patients, 7.0% of patients were treated at a DCC. Median patient age and complexity of surgical procedures were comparable among DCCs and non-DCCs (all p > 0.05). Overall complications (16.5% vs. 23.6%), 90-day readmission (26.2% vs. 30.2%), and 90-day mortality (3.0% vs. 8.7%) were lower at DCCs compared with non-DCCs (all p < 0.001). In addition, long-term hazards of death among patients undergoing hepatectomy [hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.54-0.75] and pancreatectomy (HR 0.66, 95% CI 0.56-0.78) were lower among patients treated at DCCs (both p < 0.05). While Medicare payments for patients undergoing pancreatic surgery (DCC: $22,200 vs. non-DCC: $22,100; p = 0.772) were comparable among DCC and non-DCC hospitals, Medicare payments for liver resection at DCCs were 13.9% lower than non-DCCs (DCC: $16,700 vs. non-DCC: $19,400; p < 0.001). CONCLUSIONS: Patients undergoing hepatopancreatic surgery at DCCs had better short- and long-term outcomes for the same/lower level of Medicare expenditure as non-DCC hospitals. DCCs provide higher-value surgical care for patients undergoing liver and pancreatic cancer operations.
doi: https://doi.org/10.1245/s10434-019-07677-1
- NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31375766
With the FDA approval of larotrectinib, NTRK fusion assessment has recently become a standard part of management for patients with locally advanced or metastatic cancers. Unlike somatic mutation assessment, the detection of NTRK fusions is not straightforward, and various assays exist at the DNA, RNA, and protein level. Here, we investigate the performance of immunohistochemistry and DNA-based next-generation sequencing to indirectly or directly detect NTRK fusions relative to an RNA-based next-generation sequencing approach in the largest cohort of NTRK fusion positive solid tumors to date. A retrospective analysis of 38,095 samples from 33,997 patients sequenced by a targeted DNA-based next-generation sequencing panel (MSK-IMPACT), 2189 of which were also examined by an RNA-based sequencing assay (MSK-Fusion), identified 87 patients with oncogenic NTRK1-3 fusions. All available institutional NTRK fusion positive cases were assessed by pan-Trk immunohistochemistry along with a cohort of control cases negative for NTRK fusions by next-generation sequencing. DNA-based sequencing showed an overall sensitivity and specificity of 81.1% and 99.9%, respectively, for the detection of NTRK fusions when compared to RNA-based sequencing. False negatives occurred when fusions involved breakpoints not covered by the assay. Immunohistochemistry showed overall sensitivity of 87.9% and specificity of 81.1%, with high sensitivity for NTRK1 (96%) and NTRK2 (100%) fusions and lower sensitivity for NTRK3 fusions (79%). Specificity was 100% for carcinomas of the colon, lung, thyroid, pancreas, and biliary tract. Decreased specificity was seen in breast and salivary gland carcinomas (82% and 52%, respectively), and positive staining was often seen in tumors with neural differentiation. Both sensitivity and specificity were poor in sarcomas. Selection of the appropriate assay for NTRK fusion detection therefore depends on tumor type and genes involved, as well as consideration of other factors such as available material, accessibility of various clinical assays, and whether comprehensive genomic testing is needed concurrently.
doi: https://doi.org/10.1038/s41379-019-0324-7
- Tumour Growth Rate as a validated early radiological biomarker able to reflect treatment-induced changes in Neuroendocrine Tumours; the GREPONET-2 study
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31375514
PURPOSE: TGR represents the percentage change in tumour volume per month (%/m). Previous results from the GREPONET study showed that TGR measured after 3 months (TGR3m) of starting systemic treatment (ST) or watch and wait (WW) was an early biomarker predicting progression-free survival (PFS) in NETs. EXPERIMENTAL DESIGN: Pts from7 centres with advanced grade(G) 1/2 NETs from the pancreas(P)/small bowel(SB) initiating ST/WW were eligible. Computed tomography (CT) / magnetic resonance imaging (MRI) performed at pre-baseline, baseline and 3(+/-1) months of study entry were retrospectively reviewed. Aim-1: explore treatment-induced changes in TGR (ΔTGR3m-BL) (paired T-test) and Aim-2: validate TGR3m (<0.8%/m vs ≥0.8%/m) as an early biomarker in an independent cohort (Kaplan-Meier/Cox Regression). RESULTS: Out of 785 pts screened, 127 were eligible. Mean (SD) TGR0 and TGR3m were 5.4%/m (14.9) and -1.4%/m (11.8), respectively. Mean(SD) ΔTGR3m-BL paired-difference was -6.8%/m(19.3) (p<0.001). Most marked ΔTGR3m-BL (mean (SD);p) were identified with targeted therapies (-11.3%/m(4.7);0.0237) and chemotherapy (-7.9%/m(3.4);0.0261). Multivariable analysis confirmed the absence of previous treatment (Odds Ratio (OR) 4.65 (95%CI 1.31-16.52); p-value0.018) and low TGR3m (continuous variable; OR 1.09 (95%CI 1.01-1.19); p-value0.042) to be independent predictors of radiological objective response. When the multivariable Cox Regression was adjusted to grade (p-value 0.004) and stage (p-value0.017), TGR3m≥0.8 (vs.<0.8) maintained its significance (p<0.001), while TGR0 and ΔTGR3m-BL did not. TGR3m was confirmed as an independent prognosis factor for PFS (external validation; Aim-2) (multivariable HR 2.21 (95%CI 1.21-3.70); p-value0.003). CONCLUSIONS: TGR has a role as biomarker for monitoring response to therapy for early prediction of PFS and radiological objective response.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0963
- Facility Type is Another Factor in the Volume-Outcome Relationship for Complex Hepatopancreatobiliary Procedures
Annals of surgical oncology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31372869
doi: https://doi.org/10.1245/s10434-019-07668-2
- Disruption of IRE1α through its kinase domain attenuates multiple myeloma
Proceedings of the National Academy of Sciences of the United States of America 2019 Aug;116(33):16420-16429
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31371506
Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1α supports protein secretion by deploying a kinase-endoribonuclease module to activate the transcription factor XBP1s. MM cells may co-opt the IRE1α-XBP1s pathway; however, the validity of IRE1α as a potential MM therapeutic target is controversial. Genetic disruption of IRE1α or XBP1s, or pharmacologic IRE1α kinase inhibition, attenuated subcutaneous or orthometastatic growth of MM tumors in mice and augmented efficacy of two established frontline antimyeloma agents, bortezomib and lenalidomide. Mechanistically, IRE1α perturbation inhibited expression of key components of the endoplasmic reticulum-associated degradation machinery, as well as secretion of Ig light chains and of cytokines and chemokines known to promote MM growth. Selective IRE1α kinase inhibition reduced viability of CD138+ plasma cells while sparing CD138- cells derived from bone marrows of newly diagnosed or posttreatment-relapsed MM patients, in both US- and European Union-based cohorts. Effective IRE1α inhibition preserved glucose-induced insulin secretion by pancreatic microislets and viability of primary hepatocytes in vitro, as well as normal tissue homeostasis in mice. These results establish a strong rationale for developing kinase-directed inhibitors of IRE1α for MM therapy.
doi: https://doi.org/10.1073/pnas.1906999116
- Comparative effectiveness of primary tumor resection in patients with stage III pancreatic adenocarcinoma
BMC cancer 2019 Aug;19(1):761
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31370893
BACKGROUND: Previous studies comparing primary tumor resection (PTR) to palliative treatment for advanced-stage pancreatic ductal adenocarcinoma (PDA) were limited by strong selection bias. We used multiple methods to control for confounding and selection bias to estimate the effect of PTR on survival for late-stage PDA. METHODS: Surveillance, Epidemiology, and End Results (SEER) 18 registry database for 2004 through 2014 was retrieved for the present study. A total of 4322 patients with stage III (AJCC, 6th) PDA were included in this study. Propensity score matching (PSM) was performed to eliminate possible bias. In addition, instrumental variable (IV) analysis was utilized to adjust for both measured and unmeasured confounders. RESULTS: A total of 4322 patients with stage III PDA including 552 (12.8%) who underwent PTR, 3770 (87.2%) without PTR, were identified. In the multivariable cohort, a clear prognostic advantage of PTR was observed in overall survival (OS) (P < 0.001) and disease-specific survival (DSS) (P < 0.001) compared to patients after non-surgery therapy. In the PSM cohort, patients in PTR group showed a better OS and DSS (both P values < 0.001) compared to patients in non-surgery group. The survival benefit of PTR for stage III PDA was not observed in the two-stage residual inclusion (2SRI) model. Estimates based on this instrument indicated that patients treated with PTR had similar OS (P = 0.448) and DSS (P = 0.719). In IV analyses stratified by chemotherapy and tumor location, patients undergoing PTR had similar OS and DSS compared to patients in non-surgery group across all subgroups. CONCLUSIONS: Survival with PTR did not differ significantly from palliative treatment in marginal patients with stage III pancreatic adenocarcinoma. High-quality randomized trials are needed to validate these results.
doi: https://doi.org/10.1186/s12885-019-5966-9
- African American women with gum disease and tooth loss face higher pancreatic cancer risk
Cancer 2019 Aug;125(16):2719
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31355935
doi: https://doi.org/10.1002/cncr.32413
- Mild maternal hyperglycemia in INSC93S transgenic pigs causes impaired glucose tolerance and metabolic alterations in neonatal offspring
Disease models & mechanisms 2019 Aug;12(8):
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31308048
Alongside the obesity epidemic, the prevalence of maternal diabetes is rising worldwide, and adverse effects on fetal development and metabolic disturbances in the offspring’s later life have been described. To clarify whether metabolic programming effects are due to mild maternal hyperglycemia without confounding obesity, we investigated wild-type offspring of INSC93S transgenic pigs, which are a novel genetically modified large-animal model expressing mutant insulin (INS) C93S in pancreatic β-cells. This mutation results in impaired glucose tolerance, mild fasting hyperglycemia and insulin resistance during late pregnancy. Compared with offspring from wild-type sows, piglets from hyperglycemic mothers showed impaired glucose tolerance and insulin resistance (homeostatic model assessment of insulin resistance: +3-fold in males; +4.4-fold in females) prior to colostrum uptake. Targeted metabolomics in the fasting and insulin-stimulated state revealed distinct alterations in the plasma metabolic profile of piglets from hyperglycemic mothers. They showed increased levels of acylcarnitines, gluconeogenic precursors such as alanine, phospholipids (in particular lyso-phosphatidylcholines) and α-aminoadipic acid, a potential biomarker for type 2 diabetes. These observations indicate that mild gestational hyperglycemia can cause impaired glucose tolerance, insulin resistance and associated metabolic alterations in neonatal offspring of a large-animal model born at a developmental maturation status comparable to human babies.
doi: https://doi.org/10.1242/dmm.039156
- Reply to Comment on Zeng et al, Spatial Distribution of Pancreatic Stones in Chronic Pancreatitis
Pancreas 2019 Aug;48(7):e59
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31306309
doi: https://doi.org/10.1097/MPA.0000000000001351
- Mathematical Model and Study Design Could Be Optimized in Spatial Distribution Analysis of Pancreatic Stones
Pancreas 2019 Aug;48(7):e58
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31306308
doi: https://doi.org/10.1097/MPA.0000000000001362
- Reply to: The Relationship of Acute Pancreatitis and Pancreatic Cancer
Pancreas 2019 Aug;48(7):e57-e58
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31306307
doi: https://doi.org/10.1097/MPA.0000000000001358
- The Relationship of Acute Pancreatitis and Pancreatic Cancer
Pancreas 2019 Aug;48(7):e57
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31306306
doi: https://doi.org/10.1097/MPA.0000000000001357
- Surgical and Oncological Outcomes of Laparoscopic Versus Open Pancreaticoduodenectomy in Patients With Pancreatic Duct Adenocarcinoma
Pancreas 2019 Aug;48(7):861-867
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31306305
It is not clear which of the 2 principal treatments for patients with pancreatic duct adenocarcinoma (PDAC), laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD), has greater safety and efficacy. We performed the present meta-analysis to assess the efficacy of both treatments for PDAC patients undergoing LPD. Multiple electronic databases were systematically searched to identify studies (up to October 2018) comparing LPD with OPD for PDAC. Short- and long-term oncological outcomes were evaluated. Six studies were qualified for inclusion criteria in this meta-analysis with a total of 9144 PDAC participants. Regarding safety, there were fewer overall postoperative complications associated with LPD (P = 0.005), but the results were similar in terms of pancreatic fistula and mortality. Laparoscopic pancreaticoduodenectomy was associated with a better trend of performance both in R0 resection (relative risk, 1.03; 95% confidence interval [CI], 1.00-1.07; P = 0.07) and preserved lymph nodes (median, 2.14; 95% CI, -0.21 to 4.49; P = 0.07). Long-term overall survival was comparable between LPD and OPD (hazard ratio, 1.03; 95% CI, 0.95-1.13; P = 0.49). In conclusion, LPD was found to be a suitable alternative to OPD in selected PDAC patients with respect to both surgical and oncological outcomes.
doi: https://doi.org/10.1097/MPA.0000000000001363
- Excess body weight at age <50 years is linked to pancreatic cancer mortality
Cancer 2019 Aug;125(15):2527
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31298753
doi: https://doi.org/10.1002/cncr.32394
- Trends in biomarker discoveries for the early detection and risk stratification of pancreatic cancer using omics studies
Expert review of molecular diagnostics 2019 Aug;19(8):651-654
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31298060
doi: https://doi.org/10.1080/14737159.2019.1643718
- Impact of Changes in the American Joint Committee on Cancer Staging Manual, Eighth Edition, for Pancreatic Ductal Adenocarcinoma
Pancreas 2019 Aug;48(7):876-882
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268985
OBJECTIVE: Consistent and reliable tumor staging is a critical factor in determining treatment strategy, selection of patients for adjuvant therapy, and for therapeutic clinical trials. The aim of this study was to evaluate the number and extent of pancreatic ductal adenocarcinoma (PDAC) cases that would have a different pT, pN, and overall stages based on the new eighth edition American Joint Committee on Cancer staging system when compared with the seventh edition. METHODS: Patients diagnosed with PDAC who underwent pancreaticoduodenectomy, total pancreatectomy, or distal pancreatectomy from 2007 to 2017 were retrospectively reviewed. A total of 340 cases were included. RESULTS: According to the seventh edition, the vast majority of tumors in our cohort were staged as pT3 tumors (88.2%). Restaging these cases with the new size-based pT system resulted in a more equal distribution among the 3 pT categories, with higher percentage of pT2 cases (55%). CONCLUSIONS: The newly adopted pT stage protocol for PDAC is clinically relevant, ensures a more equal distribution among different stages, and allows for a significant prognostic stratification. In contrast, the new pN classification (pN1 and pN2) based on the number of positive lymph nodes failed to show survival differences and remains controversial.
doi: https://doi.org/10.1097/MPA.0000000000001349
- The Surveillance Patterns of Incidentally Detected Pancreatic Cysts Vary Widely and Infrequently Adhere to Guidelines
Pancreas 2019 Aug;48(7):883-887
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268984
OBJECTIVES: We aimed to determine incidental pancreatic cyst (“cyst”) surveillance patterns, predictors of receiving surveillance, and guideline adherence. METHODS: We performed a retrospective cohort study of all patients receiving longitudinal care at a single tertiary care center with a newly diagnosed incidental pancreatic cyst over a 2-year period (2010-2011). All follow-up care was abstracted over a 5-year period. RESULTS: Of 3241 eligible imaging studies reviewed, 100 patients with newly diagnosed incidental cysts eligible for surveillance were identified. A majority (53%) received no follow-up. We identified 4 predictors of cyst surveillance: radiology report conclusion mentioning the cyst (odds ratio [OR], 14.9; 95% confidence interval [CI], 1.9-119) and recommending follow-up (OR, 5.5; 95% CI, 2.1-13.9), pancreas main duct dilation (OR, 10.7; 95% CI, 1.3-89), and absence of multiple cysts (OR, 2.5; 95% CI, 1.1-10.0). Of the 47 patients who received surveillance, 66% met minimum surveillance imaging intervals of at least one guideline. Conversely, 21% of patients met the criteria for overutilization in at least one guideline. CONCLUSIONS: Although guidelines recommend that surgically fit patients with incidental cysts undergo surveillance, most patients receive no follow-up. When follow-up occurs, surveillance patterns vary widely and infrequently conform to guidelines. Interventions to reduce care variation require study.
doi: https://doi.org/10.1097/MPA.0000000000001352
- Alternate Week Gemcitabine and Capecitabine: An Effective Treatment for Patients With Pancreatic Adenocarcinoma
Pancreas 2019 Aug;48(7):927-930
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268983
OBJECTIVE: Determine whether a regimen of fixed dose rate gemcitabine plus capecitabine is effective and tolerable for advanced pancreatic adenocarcinoma. METHODS: We performed a retrospective analysis of 62 patients with locally advanced or metastatic pancreatic adenocarcinoma treated at the University of California San Francisco between 2008 and 2016. Treatment was an alternate week schedule of fixed dose rate 1000 mg/m gemcitabine and capecitabine 1000 mg/m (58 patients), 1200 mg/m (12 patients), or 650 mg/m (1 patient) for intended 12 cycles. We evaluated overall survival (OS), progression-free survival (PFS), radiologic response, and adverse events necessitating treatment modification. RESULTS: For metastatic patients, median OS was 10.3 months (95% confidence interval [CI], 6.7-12.1 months), and PFS was 5.6 months (95% CI, 2.6-7.7 months). In locally advanced patients, OS was 12.0 months (95% CI, 4.9-17.1 months), and PFS was 5.4 months (95% CI, 2.5-9.4 months). Radiologic response for metastatic disease (42 patients) was 19% objective response, 45% stable disease, and 36% progressive disease. Treatment required modification for 22 patients due to adverse events, most frequently hand-foot syndrome (18 patients). CONCLUSIONS: Alternate week schedule of fixed dose rate gemcitabine and capecitabine was active and tolerable for advanced pancreatic adenocarcinoma. Overall survival and PFS were comparable to first-line treatments. Importantly, adverse effects appear less severe than first-line treatments.
doi: https://doi.org/10.1097/MPA.0000000000001354
- Induction Therapy in Localized Pancreatic Cancer
Pancreas 2019 Aug;48(7):913-919
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268982
OBJECTIVES: Pancreatic cancer (PDAC) with localized stage includes resectable (RPC), borderline resectable (BRPC), or locally advanced unresectable (LAPC). Standard of care for RPC is adjuvant chemotherapy. There are no prospective randomized trials for best treatment of BRPC and LAPC. We evaluate the impact of induction chemotherapy on localized PDAC. METHODS: Charts of PDAC patients treated at Emory University between 2009 and 2016 were reviewed. The primary end point was overall survival (OS). RESULTS: A total of 409 localized PDACs were identified. Resectability was prospectively determined at a multidisciplinary tumor conference. Median age was 67 years (range, 30-92 years), 49% were male, 66% were white, 171 had RPC, 131 had BRPC, and 107 had LAPC. Median OSs for RPC, BRPC, and LAPC were 19.5, 16.1, and 12.7 months, respectively. Type of chemotherapy and age were predictors of OS. Induction chemotherapy was used in 106 with BRPC (81%) and 74 with RPC (56.5%); patients with BRPC who received combination chemotherapy and resection had a median OS of 31.5 compared with 19.5 months in patients with RPC (P = 0.0049). Patients with LAPC had a median OS of 12.7 months. CONCLUSIONS: In patients with BRPC who undergo resection after induction treatment, the OS was significantly better than in patients with RPC. Neoadjuvant treatment should be considered for all localized PDACs.
doi: https://doi.org/10.1097/MPA.0000000000001353
- Acute Recurrent and Chronic Pancreatitis as Initial Manifestations of Cystic Fibrosis and Cystic Fibrosis Transmembrane Conductance Regulator-Related Disorders
Pancreas 2019 Aug;48(7):888-893
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268981
OBJECTIVES: Recurrent pancreatitis is considered a rare manifestation of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction; this case series highlights that pancreatitis can be a presenting symptoms of cystic fibrosis (CF) or a CFTR-related disorder (CFTR-RD). METHODS: Retrospective review of patients younger than 30 years diagnosed as having acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP) and subsequently diagnosed as having CF or CFTR-RD. RESULTS: Among 18 patients, median time from diagnosis of ARP/CP to diagnosis of CF was 0.4 years (range, 0-33 years). Eight were classified as having CF by elevated sweat chloride testing (SCT). Five had intermediate SCT (30-59 mmol/L) with 2 pathogenic mutations. Five had CFTR-RD with intermediate SCT and 0 to 1 pathogenic mutations. Eight patients (44%) had exocrine pancreatic insufficiency, and pancreatic fluid collections were more common in this group. Based on the CFTR mutation, 6 patients were eligible for CFTR potentiator therapy, although none received it during the study period. Nine of the 18 had ≥1 other likely CF manifestations, including sinusitis (33%), nasal polyps (11%), pneumonia (22%), and gallbladder disease (22%). CONCLUSIONS: Cystic fibrosis or CFTR-RD can present as ARP/CP. Complete diagnostic testing for CFTR-RD in patients with ARP/CP will broaden treatment options and help to identify comorbid illness.
doi: https://doi.org/10.1097/MPA.0000000000001350
- Significance of Lymph Node Metastasis in Resectable Well-differentiated Pancreatic Neuroendocrine Tumor
Pancreas 2019 Aug;48(7):943-947
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268980
OBJECTIVES: Understanding the effect of lymph node metastasis (LNM) on prognosis in pancreatic neuroendocrine neoplasm is helpful for surgery and follow-up. In this study, we investigated the significance of LNM in well-differentiated pancreatic neuroendocrine tumors (PanNETs) according to the World Health Organization 2017 classification. METHODS: We retrospectively collected data for 95 consecutive patients with PanNET who underwent pancreatic resection with curative intent between January 2008 and December 2017 at 6 institutions. The clinicopathological factors were compared in patients with and without LNM, and prognostic factors were analyzed. RESULTS: Lymph node metastasis was significantly associated with malignant potential of PanNET, such as larger tumor size, higher Ki-67 index, higher tumor grade, and higher incidence of lymphatic, vessel, and neural invasion. Lymph node metastasis was also associated with disease-free but not overall survival. Multivariate analysis identified NET grade 2 (G2) and G3 as independent risk factors for recurrence after curative resection. CONCLUSIONS: World Health Organization 2017 classification was the most independent prognostic factor in patients with resectable well-differentiated PanNETs. Patients with G2 and higher-grade tumors require lymph node dissection to improve prognosis.
doi: https://doi.org/10.1097/MPA.0000000000001355
- Gastric Emptying and Distal Gastrectomy Independently Enhance Postprandial Glucagon-Like Peptide-1 Release After a Mixed Meal and Improve Glycemic Control in Subjects Having Undergone Pancreaticoduodenectomy
Pancreas 2019 Aug;48(7):953-957
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268979
OBJECTIVES: New-onset diabetes frequently resolves after pancreaticoduodenectomy (PD). Glucagon-like peptide-1 (GLP-1) conceivably is involved as its release is enhanced by rapid gastric emptying and distal bowel exposure to nutrients. We aimed at studying factors associated with GLP-1 release after PD. METHODS: Fifteen PD subjects with distal gastrectomy (Whipple) and 15 with pylorus preservation were evaluated. A test meal containing 1 g paracetamol to measure gastric emptying was ingested. Blood for the measurement of paracetamol, glucose, insulin, and GLP-1 was drawn at baseline and 10, 20, 30, 60, 90, 120, 150, and 180 minutes thereafter. The Matsuda index of insulin sensitivity was calculated. RESULTS: In univariate analysis, gastric emptying correlated with GLP-1. Glucagon-like peptide-1 responses to the modes of operation did not differ. Multiple regression analysis confirmed gastric emptying and Whipple versus pylorus-preserving pancreaticoduodenectomy as independent predictors of GLP-1 release. The Matsuda index of insulin sensitivity correlated with GLP-1 concentrations and inversely with body mass index. Patients after Whipple procedure revealed lower glycated hemoglobin as compared with pylorus-preserving pancreaticoduodenectomy. CONCLUSIONS: Following PD, the postprandial GLP-1 release seems to be enhanced by rapid gastric emptying and to improve insulin sensitivity. Partial gastrectomy versus pylorus preservation enhanced the release of GLP-1, conceivably because of greater distal bowel exposure to undigested nutrients.
doi: https://doi.org/10.1097/MPA.0000000000001361
- Endogenous Gastrin Collaborates With Mutant KRAS in Pancreatic Carcinogenesis
Pancreas 2019 Aug;48(7):894-903
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268978
OBJECTIVE: The KRAS gene is the most frequently mutated gene in pancreatic cancer, and no successful anti-Ras therapy has been developed. Gastrin has been shown to stimulate pancreatic cancer in an autocrine fashion. We hypothesized that reactivation of the peptide gastrin collaborates with KRAS during pancreatic carcinogenesis. METHODS: LSL-Kras; P48-Cre (KC) mutant KRAS transgenic mice were crossed with gastrin-KO (GKO) mice to develop GKO/KC mice. Pancreata were examined for 8 months for stage of pancreatic intraepithelial neoplasia lesions, inflammation, fibrosis, gastrin peptide, and microRNA expression. Pancreatic intraepithelial neoplasias from mice were collected by laser capture microdissection and subjected to reverse-phase protein microarray, for gastrin and protein kinases associated with signal transduction. Gastrin mRNA was measured by RNAseq in human pancreatic cancer tissues and compared to that in normal pancreas. RESULTS: In the absence of gastrin, PanIN progression, inflammation, and fibrosis were significantly decreased and signal transduction was reversed to the canonical pathway with decreased KRAS. Gastrin re-expression in the PanINs was mediated by miR-27a. Gastrin mRNA expression was significantly increased in human pancreatic cancer samples compared to normal human pancreas controls. CONCLUSIONS: This study supports the mitogenic role of gastrin in activation of KRAS during pancreatic carcinogenesis.
doi: https://doi.org/10.1097/MPA.0000000000001360
- New-Onset Diabetes Mellitus After Chronic Pancreatitis Diagnosis: A Systematic Review and Meta-analysis
Pancreas 2019 Aug;48(7):868-875
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268977
OBJECTIVES: The aim of this study was to assess the occurrence of new-onset diabetes mellitus (DM) after chronic pancreatitis (CP) diagnosis via systematic review and meta-analysis. METHODS: A systematic review of literature and meta-analysis of relevant reports were performed. The primary outcome measures studied were newly diagnosed DM and DM treated with insulin. For the binary outcomes, pooled prevalence and 95% confidence interval (CI) were calculated. METHODS: Fifteen studies involving 8970 patients were eligible. The incidence of new-onset DM after CP diagnosis was 30% (95% CI, 27%-33%). Among all patients, 17% (95% CI, 13%-22%) developed insulin-dependent new-onset DM. The prevalence of newly diagnosed DM after CP diagnosis increased from 15% within 36 months to 33% after 60 months. The proportion of alcoholic CP, sex, age, and body mass index had minimal effect on the studied outcomes. CONCLUSIONS: This systematic review identified a clinically relevant risk of new-onset DM after CP diagnosis. Therefore, patients should be informed of the risk of DM and monitored.
doi: https://doi.org/10.1097/MPA.0000000000001359
- The Importance of a Conjoint Analysis of Tumor-Associated Macrophages and Immune Checkpoints in Pancreatic Cancer
Pancreas 2019 Aug;48(7):904-912
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268976
OBJECTIVES: Tumor-associated macrophages are dominant players in establishing the inmmunosuppressive microenvironment in pancreatic ductal adenocarcinoma (PDAC). Immune checkpoint inhibitor monotherapy has achieved limited clinical effectiveness. To date, the interaction of macrophages and checkpoint regulators and their correlation with clinicopathologic characteristics in PDAC have been largely unavailable. METHODS: Macrophages and immune checkpoint expression were assessed by immunohistochemistry from 80 PDAC samples. Clinicopathologic features and the prognostic value of each marker were evaluated. In vitro changes in the expression of immune markers in cocultured macrophages and PDAC cells were detected by Western blot and immunosorbance assays. RESULTS: The macrophages marker CD163 and the checkpoint marker programmed death-ligand 1 (PD-L1) remained as the independent prognostic factors for overall survival (hazard ratio, 2.543; P = 0.017 and hazard ratio, 2.389; P = 0.021). Furthermore, integrated analysis of CD163 and PD-L1 served as more optimal indicators of survival (P = 0.000). In vitro coculture of macrophages and PDAC cells significantly increased the expression of CD163 and PD-L1, compared with monocultured counterpart (P < 0.05). CONCLUSIONS: Combined analysis of CD163 and PD-L1 was enhanced indicators of survival in PDAC patients. The interaction of macrophages and immune checkpoints implied the value of the combination therapy.
doi: https://doi.org/10.1097/MPA.0000000000001364
- Correlation of DOTATOC Uptake and Pathologic Grade in Neuroendocrine Tumors
Pancreas 2019 Aug;48(7):948-952
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268975
OBJECTIVES: Gallium (Ga)-DOTATOC is a somatostatin analog used to detect neuroendocrine tumors (NETs). Ki-67 proliferation index (Ki-67 PI) has been established as a prognostic factor in NETs. We aimed to evaluate whether a correlation exists between Ki-67 PI and somatostatin receptor positron emission tomography (SSTR-PET) uptake. METHODS: We retrospectively reviewed 238 DOTATOC PET scans between 2014 and 2016. Patients were excluded if DOTATOC PET was performed more than 365 days from the date of biopsy. Maximum standardized uptake values (SUVmax) of SSTR-PET from biopsied lesions were measured and correlated with Ki-67 PI using the Pearson correlation coefficient. RESULTS: Among 110 lesions from 90 patients, DOTATOC PET had 92.7% sensitivity and 100% specificity (102 true positives, 8 false negatives) for detection of NETs. Among 63 lesions from 54 patients with Ki-67 PI available, there were 27 grade 1 lesions [median Ki-67 PI, 1.0%; interquartile range (IQR), 1.0-2.0], 30 grade 2 lesions (median, Ki-67 PI 7.5%; IQR, 5-10), and 6 grade 3 lesions (median Ki-67 PI, 30%; IQR, 26-34). There was a correlation between Ki-67 PI and SUVmax (r = -0.3, P = 0.018). CONCLUSIONS: Our analysis demonstrates an inverse correlation between Ki-67 PI and SUVmax in NETs. Somatostatin receptor-PET provides additional information that can help guide management of NETs.
doi: https://doi.org/10.1097/MPA.0000000000001356
- Diagnostic and Management Challenges in Vasoactive Intestinal Peptide Secreting Tumors: A Series of 15 Patients
Pancreas 2019 Aug;48(7):934-942
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268974
OBJECTIVES: Vasoactive intestinal peptide-secreting tumors (VIPomas) are rare functioning neuroendocrine tumors often characterized by a difficult-to-control secretory syndrome and high potential to develop metastases. We hereby present the characteristics of 15 cases of VIPomas and provide a recent literature review. METHODS: This was a retrospective data analysis of 15 patients with VIPoma from 3 different centers and literature research through PubMed database during the last 10 years. RESULTS: Fifteen patients with VIPomas (9 with hepatic metastases at diagnosis) with watery diarrhea and raised VIP levels were studied. Ten patients (67%) had grade 2 tumors, 6 of 15 had localized disease and underwent potentially curative surgery, whereas the remaining 9 received multiple systemic therapies; 3 patients died during follow-up. The median overall survival was 71 months (range, 41-154 months). Patients who were treated with curative surgery (n = 7) had longer median overall survival compared with patients who were treated with other therapeutic modalities (44 vs 33 months). CONCLUSIONS: The management of VIPomas is challenging requiring the application of multiple treatment modalities. Patients who underwent surgical treatment with curative intent appear to have higher survival rate. Central registration and larger prospective studies are required to evaluate the effect of currently employed therapies in these patients.
doi: https://doi.org/10.1097/MPA.0000000000001347
- Complications to Chronic Pancreatitis and Etiological Risk Factors: A Continental Divide?
The American journal of gastroenterology 2019 Aug;114(8):1353
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31211705
doi: https://doi.org/10.14309/ajg.0000000000000302
- Benchmark, Textbook or Optimal Pancreatic Surgery?
Annals of surgery 2019 Aug;270(2):219-220
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31188222
doi: https://doi.org/10.1097/SLA.0000000000003377
- Comparisons of Outcomes of Real-World Patients With Advanced Pancreatic Cancer Treated With FOLFIRINOX Versus Gemcitabine and Nab-Paclitaxel: A Population-Based Cohort Study
Pancreas 2019 Aug;48(7):920-926
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31180981
OBJECTIVES: The aim of this study was to compare the efficacy and safety of FOLFIRINOX (5-FU/leucovorin, irinotecan, and oxaliplatin) and gemcitabine/nab-paclitaxel (GnP) in patients with advanced pancreatic cancer. METHODS: Patients with newly diagnosed advanced pancreatic cancer in Saskatchewan, Canada, from 2011 to 2016, who received FOLFIRINOX or GnP were assessed. A Cox proportional multivariate analysis was performed to evaluate prognostic variables. RESULTS: One hundred nineteen eligible patients with median age of 61 years and male/female ratio of 70:49 were identified. Seventy-seven percent had metastatic disease. Of 119 patients, 86 (72%) received FOLFIRINOX and 33 (28%) were treated with GnP. Median progression-free survival of the FOLFIRINOX group was 6.0 months [95% confidence interval (CI), 4.5-7.5] versus 4.0 months (95% CI, 2.9-5.1) with GnP (P = 0.39). The median overall survival of the FOLFIRINOX group was 9.0 months (95% CI, 7-11) compared with 9.0 months (95% CI, 4.2-13.8) with GnP (P = 0.88). On multivariate analysis, albumin [hazard ratio (HR), 0.63; 95% CI, 0.41-0.97], male sex (HR, 0.65; 95% CI, 0.43-0.97), and second-line therapy (HR, 0.50; 95% CI, 0.28-0.86) were correlated with survival. CONCLUSIONS: Our results showed that real-world patients with advanced pancreatic cancer treated with FOLFIIRNOX or GnP had comparable survival with different safety profile.
doi: https://doi.org/10.1097/MPA.0000000000001340
- Differences in Pancreatic Cancer Incidence Rates and Temporal Trends Across Asian Subpopulations in California (1988-2015)
Pancreas 2019 Aug;48(7):931-933
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31180980
OBJECTIVE: Ethnic disparities in pancreatic cancer (PanCan) incidence exist, but little is known about incidence trends in heterogeneous Asian Americans. We examined PanCan incidence and temporal patterns among detailed ethnic populations, including Asian American subgroups. METHODS: A total of 71,099 invasive exocrine PanCan cases were identified using the California Cancer Registry between 1988 and 2015. Cases were grouped into mutually exclusive groups of non-Hispanic (NH) white, NH black, Hispanic, NH Asian/Pacific Islander (API), and NH American Indian/Alaska Native (AIAN). Asians were further identified by specific ethnicity. RESULTS: The age-adjusted incidence rates (AAIRs, per 100,000) of PanCan varied significantly across racial/ethnic groups, ranging from the highest of 10.4 in NH blacks to 7.6 in NH whites, 7.1 in Hispanics, 6.2 in NH APIs, and to the lowest of 5.2 in NH AIAN. Despite the relatively low rate in the NH APIs, the rates across Asian subgroups varied significantly, with rates similar to NH whites in Japanese (8.1) and Koreans (7.5) to the low rate in South Asians (4.4). CONCLUSIONS: Significant heterogeneity of PanCan incidence in disaggregated Asian Americans is a novel finding. These results fill a gap regarding PanCan burden in Asian Americans and underscore the importance of disaggregating ethnic populations in cancer research.
doi: https://doi.org/10.1097/MPA.0000000000001337
- Oncogenic NRG1 Fusions: A New Hope for Targeted Therapy in Pancreatic Cancer
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;25(15):4589-4591
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31164372
Approximately 8%-10% of pancreatic ductal adenocarcinoma cases are KRAS wild type. In a subset of these tumors, NRG1 gene fusions have been identified as targetable oncogenic drivers, a discovery that highlights the importance of deep molecular characterization for KRAS wild-type pancreatic cancers and provides a novel treatment strategy in this disease.See related article by Jones et al., p. 4674.
doi: https://doi.org/10.1158/1078-0432.CCR-19-1280
- Proton Radiotherapy for Isolated Local Recurrence of Primary Resected Pancreatic Ductal Adenocarcinoma
Annals of surgical oncology 2019 Aug;26(8):2587-2594
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31147994
BACKGROUND: The optimal treatment for isolated local recurrence (ILR) of pancreatic adenocarcinoma (PDAC) after surgical resection remains unclear. This study aimed to evaluate the safety and efficacy of proton radiotherapy (PRT) for ILR of PDAC after surgery. METHODS: The medical records of patients with ILR of PDAC after surgery who underwent proton beam therapy between 2011 and 2015 at Hyogo Ion Beam Medical Center were retrospectively studied. RESULTS: The study analyzed 30 patients (14 women and 16 men) with a median age of 65 years (range 38-81 years) who had initially undergone pancreatoduodenectomy (n = 23) or distal pancreatectomy (n = 7) for their primary tumors. Upon ILR, PRT was administered with a median total cumulative dose of 67.5 gray equivalent (GyE) (range 50-67.5 GyE) using 19 to 25 fractions. For 25 patients, concurrent chemotherapy was administered using gemcitabine (n = 18) or S-1 (n = 7). Four patients (13.3%) experienced acute grade ≥ 3 gastrointestinal toxicities. After a median follow-up period of 17.6 months (range 2.1-50.4 months), 23 patients had experienced tumor progression and 10 had died. Nine patients (30%) experienced local tumor progression. The median overall, progression-free, and local progression-free survival rates were 26.1, 12.3, and 41.2 months, respectively. Pre-PRT serum levels of cancer antigen 19-9 higher than 100 U/mL and duke pancreatic monoclonal antigen type 2 higher than 150 U/mL were significantly associated with shorter progression-free survival rates. CONCLUSIONS: Proton radiotherapy for ILR of PDAC after surgery is well tolerated and produces good locoregional control and should be considered for eligible patients.
doi: https://doi.org/10.1245/s10434-019-07471-z
- Circulating Tumor DNA as a Clinical Test in Resected Pancreatic Cancer
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;25(16):4973-4984
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31142500
PURPOSE: In research settings, circulating tumor DNA (ctDNA) shows promise as a tumor-specific biomarker for pancreatic ductal adenocarcinoma (PDAC). This study aims to perform analytical and clinical validation of a KRAS ctDNA assay in a Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathology-certified clinical laboratory. EXPERIMENTAL DESIGN: Digital-droplet PCR was used to detect the major PDAC-associated somatic KRAS mutations (G12D, G12V, G12R, and Q61H) in liquid biopsies. For clinical validation, 290 preoperative and longitudinal postoperative plasma samples were collected from 59 patients with PDAC. The utility of ctDNA status to predict PDAC recurrence during follow-up was assessed. RESULTS: ctDNA was detected preoperatively in 29 (49%) patients and was an independent predictor of decreased recurrence-free survival (RFS) and overall survival (OS). Patients who had neoadjuvant chemotherapy were less likely to have preoperative ctDNA than were chemo-naïve patients (21% vs. 69%; P < 0.001). ctDNA levels dropped significantly after tumor resection. Persistence of ctDNA in the immediate postoperative period was associated with a high rate of recurrence and poor median RFS (5 months). ctDNA detected during follow-up predicted clinical recurrence [sensitivity 90% (95% confidence interval (CI), 74%-98%), specificity 88% (95% CI, 62%-98%)] with a median lead time of 84 days (interquartile range, 25-146). Detection of ctDNA during postpancreatectomy follow-up was associated with a median OS of 17 months, while median OS was not yet reached at 30 months for patients without ctDNA (P = 0.011). CONCLUSIONS: Measurement of KRAS ctDNA in a CLIA laboratory setting can be used to predict recurrence and survival in patients with PDAC.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0197
- Controversies on the endoscopic and surgical management of pain in patients with chronic pancreatitis: pros and cons!
Gut 2019 08;68(8):1343-1351
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31129569
doi: https://doi.org/10.1136/gutjnl-2019-318742
- Stromal hyaluronan accumulation is associated with low tumor grade and nodal metastases in pancreatic ductal adenocarcinoma
Human pathology 2019 Aug;90():37-44
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31121193
Pancreatic ductal adenocarcinoma is an aggressive malignancy characterized by abundant desmoplastic stroma. Hyaluronan is a prominent stromal component of pancreatic ductal adenocarcinoma and is associated with unique clinical-pathological profiles in other tumor types. The current study aimed to delineate clinical and pathological features associated with hyaluronan accumulation in pancreatic ductal adenocarcinoma using a novel hyaluronan-binding assay currently being used in a clinical trial targeting hyaluronan. Sixty-four formalin-fixed, paraffin-embedded samples of pancreatic ductal adenocarcinomas from 49 patients treated at a single tertiary care hospital were stained. Fifty-two percent of tumors had high levels of hyaluronan. High levels were associated with low tumor grade and lymph node metastases, novel associations not previously seen in pancreatic ductal adenocarcinoma. This study has elucidated a novel clinical-pathological profile in pancreatic ductal adenocarcinomas using a new assay, suggesting hyaluronan may act as a biomarker for a subset of pancreatic tumors that could be targeted by hyaluronan-degrading agents.
doi: https://doi.org/10.1016/j.humpath.2019.05.004
- Arginine Starvation and Docetaxel Induce c-Myc-Driven hENT1 Surface Expression to Overcome Gemcitabine Resistance in ASS1-Negative Tumors
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;25(16):5122-5134
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31113844
PURPOSE: The response to acute and long-term arginine starvation results in a conditional adaptive metabolic reprogramming that can be harnessed for therapeutic opportunities in ASS1-negative tumors. Here, we investigate the underlying biology of priming ASS1- tumors with arginine deiminase (ADI-PEG20) before treatment with gemcitabine (GEM) and docetaxel (DTX) in sarcoma, pancreatic cancer, and melanoma cell lines. EXPERIMENTAL DESIGN: ASS1- tumor cell lines were treated to create LTAT (long-term ADI treated) cell lines (ASS1+) and used for drug combination studies. Protein expression of ASS1, dCK, RRM2, E2F1, c-MYC, and hENT1 was measured. c-MYC activity was determined, live-cell immunofluorescent studies for hENT1, uptake assays of FITC-cytosine probe, and rescue studies with a c-MYC inhibitor were all determined in the presence or absence of the ADI-PEG20:GEM:DTX. RESULTS: In examining modulations within the pyrimidine pathway, we identified that the addition of DTX to cells treated with ADI-PEG20 resulted in translocation of stabilized c-Myc to the nucleus. This resulted in an increase of hENT1 cell-surface expression and rendered the cells susceptible to GEM. In vivo studies demonstrate that the combination of ADI-PEG20:GEM:DTX was optimal for tumor growth inhibition, providing the preclinical mechanism and justification for the ongoing clinical trial of ADI-PEG20, GEM, and DTX in sarcoma. CONCLUSIONS: The priming of tumors with ADI-PEG20 and DTX results in the stabilization of c-MYC potentiating the effect of GEM treatment via an increase in hENT1 expression. This finding is applicable to ASS1-deficient cancers that are currently treated with GEM.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0206
- RAS Mutation Decreases Overall Survival After Optimal Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy of Colorectal Peritoneal Metastasis: A Modification Proposal of the Peritoneal Surface Disease Severity Score
Annals of surgical oncology 2019 Aug;26(8):2595-2604
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31111351
BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are currently the most accepted treatment for peritoneal metastases from colorectal cancer. Restrictive selection criteria are essential to obtain the best survival benefits for this complex procedure. The most widespread score for patient selection, the peritoneal surface disease severity score (PSDSS), does not include current biological factors that are known to influence on prognosis. We investigated the impact of including RAS mutational status in the selection criteria for these patients. METHODS: We studied the risk factors for survival by multivariate analysis using a prospective database of consecutive patients with carcinomatosis from colorectal origin treated by CRS and HIPEC in our unit from 2009 to 2017. The risk factors obtained were validated in a multicentre, international cohort, including a total of 520 patients from 15 different reference units. RESULTS: A total of 77 patients were selected for local análisis. Only RAS mutational status (HR: 2.024; p = 0.045) and PSDSS stage (HR: 2.90; p = 0.009) were shown to be independent factors for overall survival. Early PSDSS stages I and II associated to RAS mutations impaired their overall survival with no significant differences with PSDSS stage III overall survival (p > 0.05). These results were supported by the international multicentre validation. CONCLUSIONS: By including RAS mutational status, we propose an updated RAS-PSDSS score that outperforms PSDSS alone providing a quick and feasible preoperative assessment of the expected overall survival for patients with carcinomatosis from colorectal origin undergone to CRS + HIPEC.
doi: https://doi.org/10.1245/s10434-019-07378-9
- Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study
The lancet. Gastroenterology & hepatology 2019 Aug;4(8):611-621
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31109808
BACKGROUND: This study aimed to assess the safety and tolerability of the immune checkpoint inhibitor nivolumab, as monotherapy or combined with chemotherapy, in Japanese patients with biliary tract cancer. METHODS: This multicentre, open-label, phase 1 trial was done at four cancer centres in Japan. Eligible patients were aged 20-79 years, had biliary tract adenocarcinoma (intrahepatic bile duct cancer, extrahepatic bile duct cancer, gallbladder cancer, or ampullary cancer), Eastern Cooperative Oncology Group performance status 0 or 1, adequate hepatic, renal, and haematological function, and tumour tissue samples for PD-L1 expression analysis. Patients with unresectable or recurrent biliary tract cancer that was refractory or intolerant to gemcitabine-based treatment regimens received nivolumab monotherapy (240 mg every 2 weeks [monotherapy cohort]). Chemotherapy-naive patients with unresectable or recurrent biliary tract cancer received nivolumab (240 mg every 2 weeks) and cisplatin (25 mg/m2) plus gemcitabine (1000 mg/m2) chemotherapy (combined therapy cohort). The primary objective was to assess tolerability and safety. The primary objective was assessed in the safety population of all patients who had received at least one dose of nivolumab. This study is registered with www.clinicaltrials.jp, number JapicCTI-153098, and follow-up is ongoing. FINDINGS: 30 patients were enrolled into each cohort between Jan 13, 2016, and April 19, 2017. Data cutoff was Aug 31, 2017. In the monotherapy cohort, the most frequently reported treatment-related adverse events were decreased appetite (five [17%]), malaise (four [13%]), and pruritus (four [13%]). Grade 3-4 treatment-related adverse events were reported by three (10%) patients (rash, maculopapular rash, and amylase increase) and treatment-related serious adverse events were reported by one (3%) patient (pleurisy). In the combined therapy cohort, the most frequently reported treatment-related adverse events were neutrophil count decrease (any grade 25 [83%]; grade 3-4 in 23 [77%] patients) and platelet count decrease (any grade 25 [83%] of 30; grade 3-4 in 15 [50%] patients). Six (20%) patients reported 11 treatment-related serious adverse events (platelet count decrease [three patients], febrile neutropenia [two patients], neutrophil count decrease, anaemia, anaphylactic reaction, decreased appetite, pyrexia, and myocarditis [one patient each]). In the monotherapy cohort, median overall survival was 5·2 months (90% CI 4·5-8·7), median progression-free survival was 1·4 months (90% CI 1·4-1·4), and one of 30 patients had an objective response. In the combined therapy cohort, median overall survival was 15·4 months (90% CI 11·8-not estimable), median progression-free survival was 4·2 months (90% CI 2·8-5·6), and 11 of 30 patients had an objective response. INTERPRETATION: Nivolumab had a manageable safety profile and signs of clinical activity in patients with unresectable or recurrent biliary tract cancer. This initial assessment of nivolumab for the treatment of advanced biliary tract cancer provides supportive evidence for future larger randomised studies of nivolumab in this difficult to treat cancer. FUNDING: Ono Pharmaceutical Co Ltd and Bristol-Myers Squibb Inc.
doi: https://doi.org/10.1016/S2468-1253(19)30086-X
- NRG1 Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;25(15):4674-4681
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31068372
PURPOSE: Gene fusions involving neuregulin 1 (NRG1) have been noted in multiple cancer types and have potential therapeutic implications. Although varying results have been reported in other cancer types, the efficacy of the HER-family kinase inhibitor afatinib in the treatment of NRG1 fusion-positive pancreatic ductal adenocarcinoma is not fully understood. EXPERIMENTAL DESIGN: Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving NRG1 received afatinib treatment, with response measured by pretreatment and posttreatment PET/CT imaging. RESULTS: Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as KRAS wild type by whole-genome sequencing. All KRAS wild-type tumors were positive for gene fusions involving the ERBB3 ligand NRG1. Two of 3 patients with NRG1 fusion-positive tumors were treated with afatinib and demonstrated a significant and rapid response while on therapy. CONCLUSIONS: This work adds to a growing body of evidence that NRG1 gene fusions are recurrent, therapeutically actionable genomic events in pancreatic cancers. Based on the clinical outcomes described here, patients with KRAS wild-type tumors harboring NRG1 gene fusions may benefit from treatment with afatinib.See related commentary by Aguirre, p. 4589.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0191
- Contemporary Improvements in Postoperative Mortality After Major Cancer Surgery are Associated with Weakening of the Volume-Outcome Association
Annals of surgical oncology 2019 Aug;26(8):2348-2356
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31065959
BACKGROUND: Regionalization of complex visceral surgery across the United States has followed identification of a volume-outcome association. However, improvements in postoperative mortality overall during the last decade may have weakened the strength of this association. METHODS: The National Cancer Database was used to identify patients undergoing colon, esophageal, liver, and pancreatic surgery from 2003 to 2011. Hospitals were divided into low-volume (< 33rd %tile), medium-volume (34-66th %tile), and high-volume (> 67th %tile) groups. Annual cancer-specific adjusted observed versus expected (O/E) ratios for 30- and 90-day mortality for each volume strata were calculated and plotted over time. RESULTS: In the year 2003, the O/E ratios decreased from low- to medium- to high-volume hospitals for all cancer surgeries for both 30- and 90-day mortality, indicating a strong volume-outcome relationship. For all volume strata, the O/E ratios trended downward from 2003 to 2011 for both 30- and 90-day mortality for all cancer surgeries. This trend was more pronounced for low- and medium-volume than for high-volume hospitals. Consequently, by 2011 the confidence intervals of the O/E ratios for the low-volume groups, and particularly for the medium-volume groups, overlapped those for the high-volume groups for most of the cancer surgeries studied. CONCLUSIONS: The volume-outcome association for major cancer surgery is dynamic and has attenuated over time primarily due to improvements in postoperative mortality at low- and medium-volume hospitals.
doi: https://doi.org/10.1245/s10434-019-07413-9
- Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;25(15):4723-4734
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31064781
PURPOSE: Targeted thorium-227 conjugates (TTC) represent a new class of molecules for targeted alpha therapy (TAT). Covalent attachment of a 3,2-HOPO chelator to an antibody enables specific complexation and delivery of the alpha particle emitter thorium-227 to tumor cells. Because of the high energy and short penetration range, TAT efficiently induces double-strand DNA breaks (DSB) preferentially in the tumor cell with limited damage to the surrounding tissue. We present herein the preclinical evaluation of a mesothelin (MSLN)-targeted thorium-227 conjugate, BAY 2287411. MSLN is a GPI-anchored membrane glycoprotein overexpressed in mesothelioma, ovarian, pancreatic, lung, and breast cancers with limited expression in healthy tissue. EXPERIMENTAL DESIGN: The binding activity and radiostability of BAY 2287411 were confirmed bioanalytically. The mode-of-action and antitumor potency of BAY 2287411 were investigated in vitro and in vivo in cell line and patient-derived xenograft models of breast, colorectal, lung, ovarian, and pancreatic cancer. RESULTS: BAY 2287411 induced DSBs, apoptotic markers, and oxidative stress, leading to reduced cellular viability. Furthermore, upregulation of immunogenic cell death markers was observed. BAY 2287411 was well-tolerated and demonstrated significant antitumor efficacy when administered via single or multiple dosing regimens in vivo. In addition, significant survival benefit was observed in a disseminated lung cancer model. Biodistribution studies showed specific uptake and retention of BAY 2287411 in tumors and enabled the development of a mechanistic pharmacokinetic/pharmacodynamic model to describe the preclinical data. CONCLUSIONS: These promising preclinical results supported the transition of BAY 2287411 into a clinical phase I program in mesothelioma and ovarian cancer patients (NCT03507452).
doi: https://doi.org/10.1158/1078-0432.CCR-18-3476
- Advanced stage at diagnosis and elevated mortality among US patients with cancer infected with HIV in the National Cancer Data Base
Cancer 2019 Aug;125(16):2868-2876
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31050361
BACKGROUND: People living with HIV (PLWH) are at an increased risk of developing several cancers, but to the authors’ knowledge less is known regarding how HIV impacts the rate of progression to advanced cancer or death. METHODS: The authors compared stage of disease at the time of presentation and mortality after diagnosis between 14,453 PLWH and 6,368,126 HIV-uninfected patients diagnosed with cancers of the oral cavity, stomach, colorectum, anus, liver, pancreas, lung, female breast, cervix, prostate, bladder, kidney, and thyroid and melanoma using data from the National Cancer Data Base (2004-2014). Polytomous logistic regression and Cox proportional hazards regression were used to evaluate the association between HIV, cancer stage, and stage-adjusted mortality after diagnosis, respectively. Regression models accounted for the type of health facility at which cancer treatment was administered and the type of individual health insurance. RESULTS: HIV-infected patients with cancer were found to be more likely to be uninsured (HIV-infected: 5.0% vs HIV-uninfected: 3.3%; P < .0001) and were less likely to have private health insurance (25.4% vs 44.7%; P < .0001). Compared with those not infected with HIV, the odds of being diagnosed at an advanced stage of disease were significantly elevated in PLWH for melanoma and cancers of the oral cavity, liver, female breast, prostate, and thyroid (odds ratio for stage IV vs stage I range, 1.24-2.06). PLWH who were diagnosed with stage I to stage III disease experienced elevated mortality after diagnosis across 13 of the 14 cancer sites evaluated, with hazard ratios ranging from 1.20 (95% CI, 1.14-1.26) for lung cancer to 1.85 (95% CI, 1.68-2.04), 1.85 (95% CI, 1.51-2.27), and 2.93 (95% CI, 2.08-4.13), respectively, for cancers of the female breast, cervix, and thyroid. CONCLUSIONS: PLWH were more likely to be diagnosed with advanced-stage cancers and to experience elevated mortality after a cancer diagnosis, even after accounting for health care-related factors.
doi: https://doi.org/10.1002/cncr.32158
- GNAS but Not Extended RAS Mutations Spectrum are Associated with a Better Prognosis in Intraductal Pancreatic Mucinous Neoplasms
Annals of surgical oncology 2019 Aug;26(8):2640-2650
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31025231
BACKGROUND: The management of intraductal papillary mucinous neoplasms (IPMNs) is mainly based on imaging features and clinical symptoms, and remains challenging. OBJECTIVE: The aim of this study was to assess GNAS, RAS family (KRAS, NRAS and HRAS), BRAF, and PIK3CA mutation status in resected IPMNs and correlate it with clinicopathological characteristics and patient survival. METHODS: Overall, 149 consecutive unselected patients who underwent pancreatectomy for IPMNs were included. After dissection from formalin-fixed and paraffin-embedded tumors, GNAS mutational screening was assessed by allelic discrimination using Taqman® probes and confirmed by SNaPshot analysis. RAS family, BRAF, and PIK3CA mutational screening was assessed by high resolution melt and Sanger sequencing. RESULTS: Gastric- and intestinal-type IPMNs were the most frequent lesions (52% and 41%, respectively). Intestinal-type IPMNs were more frequently associated high-grade dysplasia (49%) and were the only IPMNs associated with colloid-type carcinoma. All pancreatobiliary IPMNs were invasive lesions, located in the main pancreatic duct. GNAS-activating mutations were strongly associated with the intestinal phenotype (p < 10-4), while RAS pathway mutations were not associated with any particular phenotype. Mutations within other members of the epidermal growth factor receptor (EGFR) pathway were very rare (2%). GNAS-mutated IPMNs were rarely invasive (11%) and almost exclusively (83%) of the colloid type. For invasive lesions, multivariate analyses determined that only node negativity was associated with improved cancer-specific survival, but, in univariate analysis, GNAS mutation was associated with prolonged survival. CONCLUSION: In patients selected for surgery, GNAS mutation analysis and tumor phenotype can help to better predict patient prognosis. In the near future, a more precise mutational analysis of IPMNs might help to better tailor their management.
doi: https://doi.org/10.1245/s10434-019-07389-6
- The Pancreas as a Site of Metastasis or Second Primary in Patients with Small Bowel Neuroendocrine Tumors
Annals of surgical oncology 2019 Aug;26(8):2525-2532
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31011904
BACKGROUND: The small bowel and pancreas are the most common primary sites of neuroendocrine tumors (NETs) giving rise to metastatic disease. Some patients with small bowel NETs (SBNETs) present with synchronous or metachronous pancreatic NETs (PNETs), and it is unclear whether these are separate primaries or metastases from one site to the other. METHODS: A surgical NET database including patients undergoing operations for SBNETs or PNETs was reviewed. Patients with synchronous or metachronous tumors in both the small bowel and pancreas were identified, and available tissues from primary tumors and metastases were examined using a 4-gene quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) panel developed for evaluating NETs of unknown primary. RESULTS: Of 338 patients undergoing exploration, 11 had NETs in both the small bowel and pancreas. Tissues from 11 small bowel tumors, 9 pancreatic tumors, and 10 metastases were analyzed. qPCR and IHC data revealed that three patients had separate SBNET and PNET primaries, and five patients had SBNETs that metastasized to the pancreas. Pancreatic tissue was unavailable in two patients, and qPCR and IHC gave discrepant results in one patient. CONCLUSIONS: NETs in both the small bowel and pancreas were found in 3% of our patients. In nearly two-thirds of evaluable patients, the pancreatic tumor was a metastasis from the SBNET primary, while in the remaining one-third of patients it represented a separate primary. Determining the origin of these tumors can help guide the choice of systemic therapy and surgical management.
doi: https://doi.org/10.1245/s10434-019-07370-3
- ASO Author Reflections: Tending Towards a Personalized Medicine for Colorectal Carcinomatosis by Adding the RAS Mutation Status in the Workup for CRS and HIPEC
Annals of surgical oncology 2019 Aug;26(8):2605-2606
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31004296
doi: https://doi.org/10.1245/s10434-019-07362-3
- Defining the Role of Lymphadenectomy for Pancreatic Neuroendocrine Tumors: An Eight-Institution Study of 695 Patients from the US Neuroendocrine Tumor Study Group
Annals of surgical oncology 2019 Aug;26(8):2517-2524
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31004295
BACKGROUND: Preoperative factors that reliably predict lymph node (LN) metastases in pancreatic neuroendocrine tumors (PanNETs) are unclear. The number of LNs needed to accurately stage PanNETs has not been defined. METHODS: Patients who underwent curative-intent resection of non-functional PanNETs at eight institutions from 2000 to 2016 were analyzed. Preoperative factors associated with LN metastases were identified. A procedure-specific target for LN retrieval to accurately stage patients was determined. RESULTS: Of 695 patients who underwent resection, 33% of tumors were proximal (head/uncinate) and 67% were distal (neck/body/tail). Twenty-six percent of patients (n = 158) had LN-positive disease, which was associated with a worse 5-year recurrence-free survival (RFS; 60% vs. 86%; p < 0.001). The increasing number of positive LNs was not associated with worse RFS. Preoperative factors associated with positive LNs included tumor size ≥ 2 cm (odds ratio [OR] 6.6; p < 0.001), proximal location (OR 2.5; p < 0.001), moderate versus well-differentiation (OR 2.1; p = 0.006), and Ki-67 ≥ 3% (OR 3.1; p < 0.001). LN metastases were also present in tumors without these risk factors: < 2 cm (9%), distal location (19%), well-differentiated (23%), and Ki-67 < 3% (16%). Median LN retrieval was 13 for pancreatoduodenectomy (PD), but only 9 for distal pancreatectomy (DP). Given that PD routinely includes a complete regional lymphadenectomy, a minimum number of LNs to accurately stage patients was not identified. However, for DP, removal of less than seven LNs failed to discriminate 5-year RFS between LN-positive and LN-negative patients (less than seven LNs: 72% vs. 83%, p = 0.198; seven or more LNs: 67% vs. 86%; p = 0.002). CONCLUSIONS: Tumor size ≥ 2 cm, proximal location, moderate differentiation, and Ki-67 ≥ 3% are preoperative factors that predict LN positivity in resected non-functional PanNETs. Given the 9-23% incidence of LN metastases in patients without such risk factors, routine regional lymphadenectomy should be considered. PD inherently includes sufficient LN retrieval, while DP should aim to remove seven or more LNs for accurate staging.
doi: https://doi.org/10.1245/s10434-019-07367-y
- Detection of NRG1 Gene Fusions in Solid Tumors
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;25(16):4966-4972
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30988082
PURPOSE: NRG1 gene fusions are rare but potentially actionable oncogenic drivers that are present in some solid tumors. Details regarding the incidence of these gene rearrangements are lacking. Here, we assessed the incidence of NRG1 fusions across multiple tumor types and described fusion partners. EXPERIMENTAL DESIGN: Tumor specimens submitted for molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory and that underwent fusion testing by anchored multiplex PCR for targeted RNA sequencing were retrospectively identified. The overall and tumor-specific incidence was noted, as was the specific fusion partner. RESULTS: Out of 21,858 tumor specimens profiled from September 2015 to December 2018, 41 cases (0.2%) harbored an NRG1 fusion. Multiple fusion partners were identified. Fusion events were seen across tumor types. The greatest incidence was in non-small cell lung cancer (NSCLC, 25), though this represented only 0.3% of NSCLC cases tested. Other tumor types harboring an NRG1 fusion included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer. CONCLUSIONS: NRG1 fusions can be detected at a low incidence across multiple tumor types with significant heterogeneity in fusion partner.See related commentary by Dimou and Camidge, p. 4865.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0160
- Tspan8 is expressed in breast cancer and regulates E-cadherin/catenin signalling and metastasis accompanied by increased circulating extracellular vesicles
The Journal of pathology 2019 Aug;248(4):421-437
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30982971
Tspan8 exhibits a functional role in many cancer types including pancreatic, colorectal, oesophagus carcinoma, and melanoma. We present a first study on the expression and function of Tspan8 in breast cancer. Tspan8 protein was present in the majority of human primary breast cancer lesions and metastases in the brain, bone, lung, and liver. In a syngeneic rat breast cancer model, Tspan8+ tumours formed multiple liver and spleen metastases, while Tspan8- tumours exhibited a significantly diminished ability to metastasise, indicating a role of Tspan8 in metastases. Addressing the underlying molecular mechanisms, we discovered that Tspan8 can mediate up-regulation of E-cadherin and down-regulation of Twist, p120-catenin, and β-catenin target genes accompanied by the change of cell phenotype, resembling the mesenchymal-epithelial transition. Furthermore, Tspan8+ cells exhibited enhanced cell-cell adhesion, diminished motility, and decreased sensitivity to irradiation. As a regulator of the content and function of extracellular vesicles (EVs), Tspan8 mediated a several-fold increase in EV number in cell culture and the circulation of tumour-bearing animals. We observed increased protein levels of E-cadherin and p120-catenin in these EVs; furthermore, Tspan8 and p120-catenin were co-immunoprecipitated, indicating that they may interact with each other. Altogether, our findings show the presence of Tspan8 in breast cancer primary lesion and metastases and indicate its role as a regulator of cell behaviour and EV release in breast cancer. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
doi: https://doi.org/10.1002/path.5281
- Laparoscopic Complete Mesocolic Excision for Double Flexural Colon Cancers
Annals of surgical oncology 2019 Aug;26(8):2516
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30927197
BACKGROUND: Laparoscopic complete mesocolic excision (CME) for hepatic or splenic flexural colon cancer is considered technically demanding. The double (hepatic and splenic) flexural colon cancers are rare, and the laparoscopic CME procedure for such disease is not standardized. METHODS: This video presents laparoscopic CME for double (hepatic and splenic) flexural colon cancers using a medial and cranial approach. RESULTS: The patient was a 60-year-old woman with the diagnosis of splenic flexure cancer (cT4N1M0) and hepatic flexure cancer (cT3N0M0). Laparoscopic subtotal colectomy was performed. First, the left colic artery was divided at its origin, and the inferior mesenteric vein also was divided at the same level. The descending mesocolon was widely separated from the retroperitoneal tissues using a medial approach. Then, lymph node dissection along the surgical trunk was performed using a cranial approach. Finally, the transverse mesocolon was divided at the inferior border of the pancreas, and CME was achieved. The specimen was extracted through a small incision at the umbilicus, and side-to-side ileo-sigmoid anastomosis was performed extracorporeally. CONCLUSIONS: The approach presented in the video might be useful for standardization of laparoscopic CME for double flexural colon cancers.
doi: https://doi.org/10.1245/s10434-019-07329-4
- Response to Comment on “Letter to Editor Re Manuscript by Bannone et al.” Ann Surg. 2018 Dec 20
Annals of surgery 2019 Aug;270(2):e60-e61
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30870179
doi: https://doi.org/10.1097/SLA.0000000000003259
- Clear Cell Variant of Solid Pseudopapillary Neoplasm of the Pancreas: A Report of a Rare Variant and Review of the Literature
International journal of surgical pathology 2019 Aug;27(5):535-540
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30845855
The clear cell variant of solid pseudopapillary neoplasm (ccSPN) of the pancreas was first described in 2006. In this article, we report a case of this rare variant and review the few published reports. Both the current and previous reports show that ccSPN has several morphologic differences from conventional SPN, including clear vacuoles, fewer pseudopapillary formations, more solid/diffuse architecture, less hemorrhage, and fewer cholesterol clefts. Some of these features peculiar to ccSPN, such as solid/diffuse architecture, have been proposed to suggest aggressive behavior, though reports of ccSPN are rare and often have limited clinical follow-up. ccSPN also appears to occur more frequently in males than conventional SPNs. These clinical and pathologic features lead to unique set of differential diagnostic considerations for ccSPN, including metastatic renal cell carcinoma, perivascular epithelial cell tumor, and clear cell variants of other carcinomas. These unique features, atypical differential, and uncertain prognostic ramifications all make ccSPN an important variant to be aware of and report.
doi: https://doi.org/10.1177/1066896919833790
- Benchmarks in Pancreatic Surgery: A Novel Tool for Unbiased Outcome Comparisons
Annals of surgery 2019 Aug;270(2):211-218
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30829701
OBJECTIVE: To use the concept of benchmarking to establish robust and standardized outcome references after pancreatico-duodenectomy (PD). BACKGROUND: Best achievable results after PD are unknown. Consequently, outcome comparisons among different cohorts, centers or with novel surgical techniques remain speculative. METHODS: This multicenter study analyzes consecutive patients (2012-2015) undergoing PD in 23 international expert centers in pancreas surgery. Outcomes in patients without significant comorbidities and major vascular resection (benchmark cases) were analyzed to establish 20 outcome benchmarks for PD. These benchmarks were tested in a cohort with a poorer preoperative physical status (ASA class ≥3) and a cohort treated by minimally invasive approaches. RESULTS: Two thousand three hundred seventy-five (38%) low-risk cases out of a total of 6186 PDs were analyzed, disclosing low in-hospital mortality (≤1.6%) but high morbidity, with a 73% benchmark morbidity rate cumulated within 6 months following surgery. Benchmark cutoffs for pancreatic fistulas (B-C), severe complications (≥ grade 3), and failure-to-rescue rate were 19%, 30%, and 9%, respectively. The ASA ≥3 cohort showed comparable morbidity but a higher in hospital-mortality (3% vs 1.6%) and failure-to-rescue rate (16% vs 9%) than the benchmarks. The proportion of benchmark cases performed varied greatly across centers and continents for both open (9%-93%) and minimally invasive (11%-62%) PD. Centers operating mostly on complex PD cases disclosed better results than those with a majority of low-risk cases. CONCLUSION: The proposed outcome benchmarks for PD, established in a large-scale international patient cohort and tested in 2 different cohorts, may allow for meaningful comparisons between different patient cohorts, centers, countries, and surgical techniques.
doi: https://doi.org/10.1097/SLA.0000000000003223
- The Impact of Preoperative Immune Modulating Nutrition on Outcomes in Patients Undergoing Surgery for Gastrointestinal Cancer: A Systematic Review and Meta-analysis
Annals of surgery 2019 Aug;270(2):247-256
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30817349
OBJECTIVE: To define the influence of preoperative immune modulating nutrition (IMN) on postoperative outcomes in patients undergoing surgery for gastrointestinal cancer. BACKGROUND: Although studies have shown that perioperative IMN may reduce postoperative infectious complications, many of these have included patients with benign and malignant disease, and the optimal timing of such an intervention is not clear. METHODS: The Embase, Medline, and Cochrane databases were searched from 2000 to 2018, for prospective randomized controlled trials evaluating preoperative oral or enteral IMN in patients undergoing surgery for gastrointestinal cancer. The primary endpoint was the development of postoperative infectious complications. Secondary endpoints included postoperative noninfectious complications, length of stay, and up to 30-day mortality. The analysis was performed using RevMan v5.3 software. RESULTS: Sixteen studies reporting on 1387 patients (715 IMN group, 672 control group) were included. Six of the included studies reported on a mixed population of patients undergoing all gastrointestinal cancer surgery. Of the remaining, 4 investigated IMN in colorectal cancer surgery, 2 in pancreatic surgery, and another 2 in patients undergoing surgery for gastric cancer. There was 1 study each on liver and esophageal cancer. The formulation of nutrition used in all studies in the treated patients was Impact (Novartis/Nestlé), which contains ω-3 fatty acids, arginine, and nucleotides. Preoperative IMN in patients undergoing surgery for gastrointestinal cancer reduced infectious complications [odds ratio (OR) 0.52, 95% confidence interval (CI) 0.38-0.71, P < 0.0001, I = 16%, n = 1387] and length of hospital stay (weighted mean difference -1.57 days, 95% CI -2.48 to -0.66, P = 0.0007, I = 34%, n = 995) when compared with control (isocaloric isonitrogeneous feed or normal diet). It, however, did not affect noninfectious complications (OR 0.98, 95% CI 0.73-1.33, P = 0.91, I = 0%, n = 1303) or mortality (OR 0.55, 95% CI 0.18-1.68, P = 0.29, I = 0%, n = 955). CONCLUSION: Given the significant impact on infectious complications and a tendency to shorten length of stay, preoperative IMN should be encouraged in routine practice in patients undergoing surgery for gastrointestinal cancer.
doi: https://doi.org/10.1097/SLA.0000000000003256
- [Microcystic serous cystadenoma: An uncommon neoplasm of pancreas. Report of two cases]
Annales de pathologie 2019 Aug;39(4):292-296
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30711334
Microcystic variant of serous cystadenoma of the pancreas is a rare neoplasm; essentially located in the body or tail of the pancreas and associated with the von Hippel-Lindau. Often, patients are asymptomatic and the neoplasm is incidentally discovered. Usually radiographic manifestations are characteristic. Histopathological examination revealed uniform clear cuboidal cells; they can be confused with other clear cell neoplasms like renal cell carcinomas, well-differentiated neuroendocrine tumors and solid pseudopapillary tumors of the pancreas. Immunohistochemistry can be help to establish the diagnosis and to remove differential diagnosis. Serous cystadenoma is a benign neoplasm whose prognosis is excellent. We herein report two cases of microcystic serous cystadenomas of the pancreas diagnosed in two asymptomatic women and review analysis in the literature to remind the main features of this lesion and the main differential diagnosis.
doi: https://doi.org/10.1016/j.annpat.2018.12.007
- Response to Comment on “Characterization and Optimal Management of High-risk Pancreatic Anastomoses During Pancreatoduodenectomy: Response to Goussous and Cunningham”
Annals of surgery 2019 Aug;270(2):e58-e59
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30499813
doi: https://doi.org/10.1097/SLA.0000000000003121
- Comment on “Interpreting Clinical Benefits of Neoadjuvant Chemoradiation With Gemcitabine Versus Upfront Surgery in Patients With Borderline Resectable Pancreatic Cancer (BRPC)”
Annals of surgery 2019 Aug;270(2):e48-e50
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30499804
doi: https://doi.org/10.1097/SLA.0000000000003115
- DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth
Gut 2019 08;68(8):1465-1476
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30343272
BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumour with a poor prognosis using current treatments. Targeted therapies may offer a new avenue for more effective strategies. Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase with contradictory roles in different tumours that is uncharacterised in PDAC. Here, we aimed to investigate the role of DYRK1A in pancreatic tumorigenesis. DESIGN: We analysed DYRK1A expression in PDAC genetic mouse models and in patient samples. DYRK1A function was assessed with knockdown experiments in pancreatic tumour cell lines and in PDAC mouse models with genetic reduction of Dyrk1a dosage. Furthermore, we explored a mechanistic model for DYRK1A activity. RESULTS: We showed that DYRK1A was highly expressed in PDAC, and that its protein level positively correlated with that of c-MET. Inhibition of DYRK1A reduced tumour progression by limiting tumour cell proliferation. DYRK1A stabilised the c-MET receptor through SPRY2, leading to prolonged activation of extracellular signal-regulated kinase signalling. CONCLUSIONS: These findings reveal that DYRK1A contributes to tumour growth in PDAC, at least through regulation of c-MET accumulation, suggesting that inhibition of DYRK1A could represent a novel therapeutic target for PDAC.
doi: https://doi.org/10.1136/gutjnl-2018-316128
- A Prospective, Randomized Phase II Study of Adjuvant Gemcitabine Versus S-1 After Major Hepatectomy for Biliary Tract Cancer (KHBO 1208): Kansai Hepato-Biliary Oncology Group
Annals of surgery 2019 Aug;270(2):230-237
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30339627
OBJECTIVE: To evaluate each arm independently and compare adjuvant gemcitabine (GEM) and S-1 chemotherapy after major hepatectomy (hemihepatectomy or trisectionectomy) for biliary tract cancer (BTC). BACKGROUND: Standardized adjuvant therapy is not performed after major hepatectomy for BTC, and we determined the recommended dose in the former study (KHBO1003). METHODS: We performed a multicenter, randomized phase II study. The primary measure was 1-year recurrence-free survival (RFS); the secondary measures were other RFS, overall survival (OS), and others. The following 6-month adjuvant chemotherapy was administered within 12 weeks of R0/1: GEM (1000 mg/m) every 2 weeks; or S-1 (80 mg/m/d) for 28 days every 6 weeks. Thirty-five patients were assigned to each arm (alpha error, 10%; beta error, 20%). RESULTS: No patients were excluded for the per-protocol analysis. There were no statistically significant differences in the patient characteristics of the 2 arms. The 1-year RFS and 1-year OS rates of the GEM arm were 51.4% and 80.0%, respectively, whereas those of the S-1 group were 62.9% and 97.1%. The comparison of the 2 arms revealed that 2-year RFS rate, 1 and 2-year OS rates, and OS curve of the S-1 arm were superior to GEM. With regard to OS, the hazard ratio of the S-1 group was 0.477 (90% confidence interval 0.245-0.927). CONCLUSION: The comparison of the survival of the 2 groups revealed that adjuvant S-1 therapy may be superior to adjuvant GEM therapy after major hepatectomy for BTC.
doi: https://doi.org/10.1097/SLA.0000000000002865
- Response to Comment on “The Virtual Hepatectomy Changed the Practice of Liver Surgery: More Details, More Significance”
Annals of surgery 2019 Aug;270(2):e33
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30138165
doi: https://doi.org/10.1097/SLA.0000000000003009
- Determinants of Severity in Acute Pancreatitis: A Nation-wide Multicenter Prospective Cohort Study
Annals of surgery 2019 Aug;270(2):348-355
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29672416
OBJECTIVE: The aim of this study was to compare and validate the different classifications of severity in acute pancreatitis (AP) and to investigate which characteristics of the disease are associated with worse outcomes. SUMMARY OF BACKGROUND DATA: AP is a heterogeneous disease, ranging from uneventful cases to patients with considerable morbidity and high mortality rates. Severity classifications based on legitimate determinants of severity are important to correctly describe the course of disease. METHODS: A prospective multicenter cohort study involving patients with AP from 23 hospitals in Spain. The Atlanta Classification (AC), Revised Atlanta Classification (RAC), and Determinant-based Classification (DBC) were compared. Binary logistic multivariate analysis was performed to investigate independent determinants of severity. RESULTS: A total of 1655 patients were included; 70 patients (4.2%) died. RAC and DBC were equally superior to AC for describing the clinical course of AP. Although any kind of organ failure was associated with increased morbidity and mortality, persistent organ failure (POF) was the most significant determinant of severity. All local complications were associated with worse outcomes. Infected pancreatic necrosis correlated with high morbidity, but in the presence of POF, it was not associated to higher mortality when compared with sterile necrotizing pancreatitis. Exacerbation of previous comorbidity was associated with increased morbidity and mortality. CONCLUSION: The RAC and DBC both signify an advance in the description and differentiation of AP patients. Herein, we describe the complications of the disease independently associated to morbidity and mortality. Our findings are valuable not only when designing future studies on AP but also for the improvement of current classifications.
doi: https://doi.org/10.1097/SLA.0000000000002766
- Survival in Locally Advanced Pancreatic Cancer After Neoadjuvant Therapy and Surgical Resection
Annals of surgery 2019 Aug;270(2):340-347
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=29596120
OBJECTIVE: The aim of the study was to identify the survival of patients with locally advanced pancreatic cancer (LAPC) and assess the effect of surgical resection after neoadjuvant therapy on patient outcomes. BACKGROUND: An increasing number of LAPC patients who respond favorably to neoadjuvant therapy undergo surgical resection. The impact of surgery on patient survival is largely unknown. MATERIALS AND METHODS: All LAPC patients who presented to the institutional pancreatic multidisciplinary clinic (PMDC) from January 2013 to September 2017 were included in the study. Demographics and clinical data on neoadjuvant treatment and surgical resection were documented. Primary tumor resection rates after neoadjuvant therapy and overall survival (OS) were the primary study endpoints. RESULTS: A total of 415 LAPC patients were included in the study. Stratification of neoadjuvant therapy in FOLFIRINOX-based, gemcitabine-based, and combination of the two, and subsequent outcome comparison did not demonstrate significant differences in OS of 331 non-resected LAPC patients (P = 0.134). Eighty-four patients underwent resection of the primary tumor (20%), after a median duration of 5 months of neoadjuvant therapy. FOLFIRINOX-based therapy and stereotactic body radiation therapy correlated with increased probability of resection (P = 0.006). Resected patients had better performance status, smaller median tumor size (P = 0.029), and lower median CA19-9 values (P < 0.001) at PMDC. Patients who underwent surgical resection had significant higher median OS compared with those who did not (35.3 vs 16.3 mo, P < 0.001). The difference remained significant when non-resected patients were matched for time of neoadjuvant therapy (19.9 mo, P < 0.001). CONCLUSIONS: Surgical resection of LAPC after neoadjuvant therapy is feasible in a highly selected cohort of patients (20%) and is associated with significantly longer median overall survival.
doi: https://doi.org/10.1097/SLA.0000000000002753
- The cost of endoscopic treatment for walled-off pancreatic necrosis
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31383574
BACKGROUND: Use of minimally invasive techniques has reduced mortality in walled-off pancreatic necrosis (WON) but may be costly. The aim of this study was to evaluate the actual costs associated with the endoscopic management of patients with WON. METHODS: We included a retrospective cohort of WON patients treated with endoscopic, transgastric drainage and necrosectomy (ETDN) during 2013-2014. Costs were calculated for six sub-areas based on a micro-costing model. Students T-test and non-parametric analysis of variance were performed to evaluate costs in relation to disease etiology and outcome. RESULTS: We included 58 patients (50% men, median age 57 years). The most common etiologies were gallstones (57%) and alcohol (19%). Nine patients (16%) died during admission. The median length of stay was 50 days (IQR 31 days). Eighteen patients (31%) needed treatment in our intensive care unit with a median length of stay of 16 days (IQR 31 days). The mean costs and standard deviation of costs (SD) per patient were: diagnostic imaging $2,431 ($2,301), laboratory tests $3,579 ($2,477), blood products $982 ($1,734), endoscopic treatment $3,794 ($1,777), medicine $5,440 ($6,656), and ward cost $41,260 ($35,854). The mean total cost was $57,486 ($46,739). Post-ERCP pancreatitis and mortality predicted higher costs. CONCLUSIONS: This study sheds light on the different costs associated with endoscopic treatment of WON. As nearly three quarters of the costs are related to ward care, initiatives aimed at reducing the length of hospital stay may have a great impact on making endoscopic treatment more cost effective.
doi: https://doi.org/10.1016/j.pan.2019.07.042
- Coexisting pancreatic serous cystadenoma and pancreatic ductal adenocarcinoma: A cytological-pathologic correlation with literature review
Annals of diagnostic pathology 2019 Jul;42():87-91
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31382079
Pancreatic serous cystadenoma (SCA) is a benign neoplastic lesion with a distinctive gross and microscopic appearance consisting of numerous thin-walled cysts lined by uniform epithelial cells with clear cytoplasm and small nuclei. The vast majority of serous cystadenomas are benign. Pancreatic SCA has rarely been reported in association with other pancreatic lesions. We present a challenging case in which a cystic and solid pancreatic mass was identified on imaging studies. FNA was performed and showed clusters of atypical cells with significant nuclear pleomorphism (>4:1), disorganized, overlapping nuclei, and prominent nucleoli. The FNA diagnosis was positive for malignancy, consistent with adenocarcinoma. The patient underwent neoadjuvant therapy and pancreaticoduodenectomy. Final pathology showed a serous cystadenoma associated with small foci of high-grade PanIN. The lack of invasive adenocarcinoma in the resection specimen was most likely due to complete response of the tumor to neoadjuvant chemoradiation therapy, but it is also possible that only high-grade PanIN was present initially. To our knowledge, this is the first reported case of SCA and high grade PanIN/PDAC that was assessed by FNA. We discuss the cytologic differential diagnosis and how to avoid potential pitfalls highlighted by this case.
doi: https://doi.org/10.1016/j.anndiagpath.2019.07.006
- The role of abdominal drainage in pancreatic resection - A multicenter validation study for early drain removal
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31378583
BACKGROUND: Abdominal drainage and the timing of drain removal in patients undergoing pancreatic resection are under debate. Early drain removal after pancreatic resection has been reported to be safe with a low risk for clinical relevant postoperative pancreatic fistula (CR-POPF) when drain amylase on POD1 is < 5000U/L. The aim of this study was to validate this algorithm in a large national cohort. METHODS: Patients registered in the Dutch Pancreatic Cancer Audit (2014-2016) who underwent pancreatoduodenectomy, distal pancreatectomy or enucleation were analysed. Data on post-operative drain amylase levels, drain removal, postoperative pancreatic fistulae were collected. Univariate and multivariate analysis using a logistic regression model were performed. The primary outcome measure was grade B/C pancreatic fistula (CR-POPF). RESULTS: Among 1402 included patients, 433 patients with a drain fluid amylase level of <5000U/L on POD1, 7% developed a CR-POPF. For patients with an amylase level >5000U/L the CR-POPF rate was 28%. When using a cut-off point of 2000U/L or 1000U/L during POD1-3, the CR-POPF rates were 6% and 5% respectively. For patients with an amylase level of >2000U/L and >1000UL during POD 1-3 the CR-POPF rates were 26% and 22% respectively (n = 223). Drain removal on POD4 or thereafter was associated with more complications (p = 0.004). Drain amylase level was shown to be the most statistically significant predicting factor for CR-POPF (Wald = 49.7; p < 0.001). CONCLUSION: Our data support early drain removal after pancreatic resection. However, a cut-off of 5000U/L drain amylase on POD1 was associated with a relatively high CR-POPF rate of 7%. A cut-off point of 1000U/L during POD1-3 resulted in 5% CR-POPF and might be a safer alternative.
doi: https://doi.org/10.1016/j.pan.2019.07.041
- Factors predicting readmission within 30 days of acute pancreatitis attack: A prospective study
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31378581
doi: https://doi.org/10.1016/j.pan.2019.07.044
- Intraductal oncocytic papillary neoplasm of the pancreas: A systematic review
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31375434
BACKGROUND: Intraductal oncocytic papillary neoplasm of the pancreas (IOPN-P) is a rare subtype of intraductal papillary mucinous neoplasm (IPMN). This study was performed to summarize the clinicopathological features and management of IOPN-P. METHODS: English-language articles were searched from MEDLINE and EMBASE from the first report of IOPN-P in 1996 until 1 May 2019 following the methodology in the PRISMA guidelines. RESULTS: In total, 66 patients from 24 full articles were included in the final data analysis. The patients’ average age was 61 years, and the male/female ratio was 1. Most lesions were large (average size, 5.50 cm), located in the pancreatic head, and found either incidentally or by uncharacteristic abdominal symptoms. IOPN-P was usually a cystic and solid lesion with or without mural nodules on radiological examination. A definitive diagnosis was often acquired from fine needle aspiration biopsy or postoperative pathology. All tumors were diagnosed as carcinoma in situ or minimally invasive carcinoma, necessitating surgical resection. The prognosis of IOPN-P was better than that of other IPMN subtypes, even when metastasis occurred. Recurrence after surgical resection of IOPN-P was rare. CONCLUSIONS: IOPN-P is rare among IPMN subtypes with unique pathological characteristics. Because of the nontypical symptoms and radiological findings, a definitive preoperative diagnosis usually depends on multimodal examinations. Management and surveillance of IOPN-P after surgical resection should be differentiated from those of other pancreatic benign cystic lesions because of its relative malignancy, but IOPN-P should also be differentiated from other IPMN subtypes and malignant cystic tumors because of its favorable prognosis.
doi: https://doi.org/10.1016/j.pan.2019.07.040
- Rosai-Dorfman Disease of the Pancreas Shows Significant Histologic Overlap With IgG4-related Disease
The American journal of surgical pathology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31368911
Rosai-Dorfman disease (RDD) is a rare entity characterized by proliferating S100-positive histiocytes. Originally described in lymph nodes, it can involve extranodal sites. Pancreatic involvement is rare, with <10 cases previously reported. Recent studies demonstrate a possible overlap between RDD and the more common IgG4-related disease (IRD), which could further complicate pathologic diagnosis. We describe distinct morphologic characteristics as well as overlapping histologic features of IRD in 5 cases of pancreatic RDD at our institution and compare these to a cohort of nonpancreatic extranodal RDD cases. All pancreatic cases were mass forming and had spindled patterns of elongated histiocytes with smaller areas of more classical appearing RDD; all cases had areas of storiform fibrosis and dense lymphoplasmacytic infiltrates with no increase in IgG4-positive plasma cells, and all cases had some degree of vasculitis (4 cases had obliterative vasculitis). Thirteen nonpancreatic extranodal RDD cases had dense lymphoplasmacytic infiltrates; most (85%) had some fibrosis with 46% showing storiform fibrosis, 85% had vasculitis with 31% demonstrating obliterative vasculitis and 2 cases had increased IgG4 staining. Extranodal (pancreatic and nonpancreatic) RDD often shows overlapping morphologic features with IRD, including lymphoplasmacytic inflammation, storiform fibrosis with elongated histiocytes and vasculitis. This can create a diagnostic challenge in the pancreas where IRD is more commonly encountered. Pathologists need to be aware that RDD can occur in the pancreas and should include RDD in the differential of any mass forming pancreatic lesion in which morphologic features of IRD are present.
doi: https://doi.org/10.1097/PAS.0000000000001334
- ZEB1 promotes inflammation and progression towards inflammation-driven carcinoma through repression of the DNA repair glycosylase MPG in epithelial cells
Gut 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31366457
OBJECTIVE: Chronic inflammation is a risk factor in colorectal cancer (CRC) and reactive oxygen species (ROS) released by the inflamed stroma elicit DNA damage in epithelial cells. We sought to identify new drivers of UC and inflammatory CRC. DESIGN: The study uses samples from patients with UC, mouse models of colitis and CRC and mice deficient for the epithelial-to-mesenchymal transition factor ZEB1 and the DNA repair glycosylase N-methyl-purine glycosylase (MPG). Samples were analysed by immunostaining, qRT-PCR, chromatin immunoprecipitation assays, microbiota next-generation sequencing and ROS determination. RESULTS: ZEB1 was induced in the colonic epithelium of UC and of mouse models of colitis. Compared with wild-type counterparts, Zeb1-deficient mice were partially protected from experimental colitis and, in a model of inflammatory CRC, they developed fewer tumours and exhibited lower levels of DNA damage (8-oxo-dG) and higher expression of MPG. Knockdown of ZEB1 in CRC cells inhibited 8-oxo-dG induction by oxidative stress (H2O2) and inflammatory cytokines (interleukin (IL)1β). ZEB1 bound directly to the MPG promoter whose expression inhibited. This molecular mechanism was validated at the genetic level and the crossing of Zeb1-deficient and Mpg-deficient mice reverted the reduced inflammation and tumourigenesis in the former. ZEB1 expression in CRC cells induced ROS and IL1β production by macrophages that, in turn, lowered MPG in CRC cells thus amplifying a positive loop between both cells to promote DNA damage and inhibit DNA repair. CONCLUSIONS: ZEB1 promotes colitis and inflammatory CRC through the inhibition of MPG in epithelial cells, thus offering new therapeutic strategies to modulate inflammation and inflammatory cancer.
doi: https://doi.org/10.1136/gutjnl-2018-317294
- Actual 10-Year Survival After Surgical Microwave Ablation for Hepatocellular Carcinoma: A Single-Center Experience in Japan
Annals of surgical oncology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31359277
BACKGROUND: Little evidence exists regarding long-term survival after microwave ablation for hepatocellular carcinoma (HCC). The aim of this study is to determine actual 10-year survival and clarify the clinicopathological features of patients surviving ≥ 10 years after surgical microwave ablation. PATIENTS AND METHODS: This retrospective study identified 459 patients who underwent surgical microwave ablation for HCC with curative intent between 2001 and 2008. We compared 100 patients who survived ≥ 10 years with 321 patients who died within 10 years. RESULTS: Median overall survival and recurrence-free survival rates were 5.5 and 2.4 years, respectively. The actual 10-year overall survival rate was 23.8%, and the actual 10-year recurrence-free survival rate was 8.1%. Multivariate analysis showed that age > 70 years [odds ratio 1.87, P = 0.029], hepatitis C virus positivity (OR 2.30, P = 0.004), Child-Pugh class B (OR 3.28, P = 0.003), and platelet count < 10 × 104 /µL (OR 1.93, P = 0.033) were independent risk factors for actual 10-year survival. During 10-year follow-up, 66% of the ≥ 10-year survivors developed recurrence, and 91% of these patients underwent further curative treatment, including hepatic resection or local ablation, for HCC recurrence. CONCLUSION: Ten-year survival after surgical microwave ablation for HCC can be expected in approximately 24% of patients, even though nearly 2/3 of our 10-year survival patients experienced recurrence. Close postoperative follow-up and further curative treatment for recurrence are important for improving long-term survival.
doi: https://doi.org/10.1245/s10434-019-07646-8
- Characterization and comparison of GITR expression in solid tumors
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31358539
PURPOSE: Determine the differential effect of a FcgR-binding, mIgG2a anti-GITR antibody in mouse tumor modelsand characterize the tumor microenvironment for the frequency of GITR expression in T cell subsets from seven different human solid tumors. EXPERIMENTAL DESIGN: For mouse experiments, wildtype C57BL/6 mice were subcutaneously injected with MC38 cells or B16 cells, and BALB/c mice were injected with CT26 cells. Mice were treated with the anti-mouse GITR agonist antibody 21B6, and tumor burden and survival were monitored. GITR expression was evaluated at the single cell level using flow cytometry (FC). 213 samples were evaluated for GITR expression by immunohistochemistry (IHC), 63 by FC and 170 by both in seven human solid tumors: advanced hepatocellular carcinoma, non-small cell lung cancer, renal cell carcinoma, pancreatic carcinoma, head and neck carcinoma, melanoma, and ovarian carcinoma. RESULTS: The therapeutic benefit of 21B6 was greatest in CT26 followed by MC38, and was least in the B16 tumor model. The frequency of CD8 T cells and effector CD4 T cells within the immune infiltrate correlated with response to treatment with GITR antibody. Analysis of clinical tumor samples showed that non-small cell lung cancer, renal cell carcinoma, and melanoma had the highest proportions of GITR-expressing cells and highest per-cell density of GITR expression on CD4-positive Foxp3 positive Tregs. IHC and FC data showed similar trends with a good correlation between both techniques. CONCLUSIONS: Human tumor data suggest that NSCLC, RCC, and melanoma should be the tumor subtypes prioritized for anti-GITR therapy development.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0289
- Fungal sinusitis in simultaneous pancreas-kidney transplant
Journal of clinical pathology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31358535
doi: https://doi.org/10.1136/jclinpath-2018-205258
- New Nodal Staging for Primary Pancreatic Neuroendocrine Tumors: A Multi-institutional and National Data Analysis
Annals of surgery 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31356277
OBJECTIVE: To determine the prognostic role of metastatic lymph node (LN) number and the minimal number of LNs for optimal staging of patients with pancreatic neuroendocrine tumors (pNETs). BACKGROUND: Prognosis relative to number of LN metastasis (LNM), and minimal number of LNs needed to evaluate for accurate staging, have been poorly defined for pNETs. METHODS: Number of LNM and total number of LN evaluated (TNLE) were assessed relative to recurrence-free survival (RFS) and overall survival (OS) in a multi-institutional database. External validation was performed using Surveillance, Epidemiology and End Results (SEER) registry. RESULTS: Among 854 patients who underwent resection, 233 (27.3%) had at least 1 LNM. Patients with 1, 2, or 3 LNM had a comparable worse RFS versus patients with no nodal metastasis (5-year RFS, 1 LNM 65.6%, 2 LNM 68.2%, 3 LNM 63.2% vs 0 LNM 82.6%; all P < 0.001). In contrast, patients with ≥4 LNM (proposed N2) had a worse RFS versus patients who either had 1 to 3 LNM (proposed N1) or node-negative disease (5-year RFS, ≥4 LNM 43.5% vs 1-3 LNM 66.3%, 0 LNM 82.6%; all P < 0.05) [C-statistics area under the curve (AUC) 0.650]. TNLE ≥8 had the highest discriminatory power relative to RFS (AUC 0.713) and OS (AUC 0.726) among patients who had 1 to 3 LNM, and patients who had ≥4 LNM in the multi-institutional and SEER database (n = 2764). CONCLUSIONS: Regional lymphadenectomy of at least 8 lymph nodes was necessary to stage patients accurately. The proposed nodal staging of N0, N1, and N2 optimally staged patients.
doi: https://doi.org/10.1097/SLA.0000000000003478
- Left-sided Portal Hypertension After Pancreaticoduodenectomy With Resection of the Portal Vein/Superior Mesenteric Vein Confluence in Patients With Pancreatic Cancer: A Project Study by the Japanese Society of Hepato-Biliary-Pancreatic Surgery
Annals of surgery 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31356273
OBJECTIVE: The aim of this study was to evaluate how often left-sided portal hypertension (LPH) develops and how LPH affects the long-term outcomes of patients with pancreatic cancer treated with pancreaticoduodenectomy (PD) and resection of the portal vein (PV)/superior mesenteric vein (SMV) confluence. SUMMARY BACKGROUND DATA: Little is known about LPH after PD with resection of the PV/SMV confluence. METHODS: Overall, 536 patients who underwent PD with PV/SMV resection were enrolled. Among them, we mainly compared the SVp group [n=285; the splenic vein (SV) was preserved] and the SVr group (n = 227; the SV was divided and not reconstructed). RESULTS: The incidence of variceal formation in the SVr group increased until 3 years after PD compared with that in the SVp group (38.7% vs 8.3%, P < 0.001). Variceal bleeding occurred in the SVr group (n = 9: 4.0%) but not in the SVp group (P < 0.001). In the multivariate analysis, the risk factors for variceal formation were liver disease, N factor, conventional PD, middle colic artery resection, and SV division. The only risk factor for variceal bleeding was SV division. The platelet count ratio at 6 months after PD was significantly lower in the SVr group than in the SVp group (0.97 vs 0.82, P < 0.001), and the spleen-volume ratios at 6 and 12 months were significantly higher in the SVr group than in the SVp group (1.38 vs 1.00 and 1.54 vs 1.09; P < 0.001 and P < 0.001, respectively). CONCLUSIONS: PD with SV division causes variceal formation, bleeding, and thrombocytopenia.
doi: https://doi.org/10.1097/SLA.0000000000003487
- Cytology with rapid on-site examination (ROSE) does not improve diagnostic yield of EUS-FNA of pancreatic cystic lesions
Diagnostic cytopathology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31356003
BACKGROUND: Cytology with rapid on-site evaluation (ROSE) has been shown to increase the diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for solid pancreatic lesions. No data exists on the need for rapid onsite cytology in the evaluation of pancreatic cystic lesions (PCLs). The purpose of this study is to determine whether onsite cytology impacts the diagnostic yield of EUS-FNA of PCLs. METHODS: We prospectively examined all patients with PCLs who underwent EUS-FNA without onsite cytology over a 6-month period and compared this to a historical cohort of patients with PCLs who underwent EUS-FNA with ROSE in the previous 6 months. Comparison was made between the two groups based upon patient demographics, EUS cyst characteristics, and FNA fluid & cytopathology results. RESULTS: A total of 100 EUS-FNA exams for PCLs were identified: 46 with ROSE and 54 without onsite cytology. The majority of cytology findings were negative or nondiagnostic, 87.0% in the ROSE group, 77.8% in the group without onsite cytology. There was no difference using EUS-FNA without onsite cytology compared to ROSE when measuring total diagnostic yield (22.2% vs 13.0%, P = .30), number of nondiagnostic specimens (50% vs 54%, P = .69), and number of needle passes (1.51 vs 1.57, P = .68). CONCLUSIONS: (a) The majority of cytology results from EUS-FNA of cystic lesions are negative or nondiagnostic. (b) Having rapid onsite cytology evaluation of cystic lesions does not affect the number of needle passes nor diagnostic yield and is thus not recommended.
doi: https://doi.org/10.1002/dc.24291
- Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet
Gastroenterology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31352001
BACKGROUND & AIMS: Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21 (FGF21), a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. METHODS: We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 non-tumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on a HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative PCR, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound GTP. RESULTS: Pancreatic tissues of mice expressed high levels of FGF21 compared with liver. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 mRNA, compared with acinar cells from control mice, partly due to downregulation of PPARG expression-a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival-only about 12% of mice developed PDACs and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle. CONCLUSIONS: Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on a HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the GTP binding capacity of RAS. FGF21 might be used in prevention or treatment of pancreatic cancer.
doi: https://doi.org/10.1053/j.gastro.2019.07.030
- Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer
The New England journal of medicine 2019 07;381(4):317-327
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31157963
BACKGROUND: Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review. RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event. CONCLUSIONS: Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. (Funded by AstraZeneca and others; POLO ClinicalTrials.gov number, NCT02184195.).
doi: https://doi.org/10.1056/NEJMoa1903387
- Response to repeat echoendoscopic celiac plexus neurolysis in pancreatic cancer patients: A machine learning approach
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31375433
BACKGROUND: /Objectives: Efficacy of repeat echoendoscopic celiac plexus neurolysis is still unclear. Aim of the study was to assess the efficacy of repeat celiac plexus neurolysis and to build an artificial neural network model able to predict pain response. METHODS: Data regarding 156 patients treated with repeat celiac plexus neurolysis between 2004 and 2019 were reviewed. Artificial neural network and logistic regression models were built to predict pain response after treatment. Performance of the models was expressed in terms of accuracy, positive predictive value, and positive likelihood ratio. RESULTS: Median age was 62 years (range 39-86) and most patients were male (66%) with pre-procedural visual analogue score 7. Fifty-one patients (32.6%) experienced treatment response, of which 6 (3.8%) complete pain suppression. Median duration of pain relief was 6 (2-8) weeks. Tumoral stage, interval from initial to repeat treatment, response to initial neurolysis, and tumor progression between the two treatments resulted as significant predictors of pain response. The performance of the artificial neural network in predicting treatment response was higher than regression model (area under the curve: 0.94, 0.89-0.97 versus 0.85, 0.78-0.89; p < 0.001). Positive predictive value and positive likelihood ratio resulted 90.3% and 19.35, respectively. Classification error rate was 5.7% with the artificial neural network compared to 14.7% of regression model (p < 0.001). These findings were confirmed through ten-fold cross validation. CONCLUSIONS: Pain response following repeat neurolysis is generally less pronounced than after initial treatment. Artificial neural network may help to identify those subjects likely to benefit from repeat neurolysis.
doi: https://doi.org/10.1016/j.pan.2019.07.038
- Characterising the impact of body composition change during neoadjuvant chemotherapy for pancreatic cancer
Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31362865
BACKGROUND: Pancreatic Cancer remains a lethal disease for the majority of patients. New chemotherapy agents such as Folfirinox offer therapeutic potential for patients who present with Borderline Resectable disease (BRPC). However, results to date are inconsistent, with factors such as malnutrition limiting successful drug delivery. We sought to determine the prevalence of sarcopenia in BRPC patients at diagnosis, and to quantify body composition change during chemotherapy. METHODS: The diagnostic/restaging CT scans of BRPC patients were analysed. Body composition was measured at L3 using Tomovision Slice-O-Matic™. Total muscle and adipose tissue mass were estimated using validated regression equations. Sarcopenia was defined as per gender- and body mass index (BMI)-specific lumbar skeletal muscle index (LSMI) and muscle attenuation reference values. RESULTS: Seventy-eight patients received neo-adjuvant chemotherapy, and 67 patients underwent restaging CT, at which point a third were deemed resectable. Half were sarcopenic at diagnosis, and sarcopenia was equally prevalent across all BMI categories.. Skeletal muscle and adipose tissue (intra-muscular, visceral and sub-cutaneous) area decreased during chemotherapy (p < 0.0001). Low muscle attenuation was observed in half of patients at diagnosis, and was associated with increased mortality risk. Loss of lean tissue parameters during chemotherapy was associated with an increased mortality risk; specifically fat-free mass, HR 1.1 (95% CI 1.03-1.17, p = 0.003) and skeletal muscle mass, HR 1.21 (95%CI 1.08-1.35, p = 0.001). CONCLUSIONS: Sarcopenia was prevalent in half of patients at the time of diagnosis with BRPC. Low muscle attenuation at diagnosis, coupled with lean tissue loss during chemotherapy, independently increased mortality risk.
doi: https://doi.org/10.1016/j.pan.2019.07.039
- Fine needle aspiration of the liver: a ten-year single institution retrospective review
Human pathology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31351156
Fine-needle aspiration (FNA) of liver masses is a minimally invasive means of evaluation, with diagnostic accuracy over 85%. Given that most of the recent literature on sampling hepatic tumors was published by radiologists and gastroenterologists, we herein conduct a 10-year retrospective review of a single institution’s cytopathology experience with the diagnosis of liver lesions. Electronic record review of the cytopathology files (CoPathPlus; Cerner Corp.) was conducted for the 10-year interval January 2007 through December 2016. All cytology specimens designated as “liver” and “FNA” were included. Associated concurrent and subsequent surgical pathology and cytopathology cases were identified. All FNA cases were organized into four diagnostic categories: positive for malignancy, atypical, negative for malignancy, and non-diagnostic. There were 713 hepatic FNAs that were categorized as follows: positive for malignancy 467 (65.5%), atypical 49 (6.9%), negative 171 (24.0%) and non-diagnostic 26 (3.6%). Metastatic tumors (95.7%) were more common that primary (4.3%). The top two metastatic primary sites were pancreas (30.1%) and colon (12.7%). A total of 166 (23.2%) cases had concurrent core needle biopsies (CNB). 111 (66.9%) were concordant with the FNA diagnosis. Of the 55 discordant cases, 43 (25.9%) had diagnostic material only on CNB and 12 (7.2%) had diagnostic material only on FNA. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 93.4%, 96.7%, 98.2%, 84.3%, and 89.3% respectively. Irrespective of endoscopic versus percutaneous approach, hepatic FNA is a sensitive and specific means of identifying metastatic and primary malignancies of the liver.
doi: https://doi.org/10.1016/j.humpath.2019.07.007
- Reappraisal of a 2-Cm Cut-Off Size for the Management of Cystic Pancreatic Neuroendocrine Neoplasms: A Multicenter International Study
Annals of surgery 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31348038
MINI: The characteristics of cystic pancreatic neuroendocrine neoplasms (cPanNENs) are largely unknown, and their clinical management remains unclear; specifically, an observational strategy for asymptomatic cPanNENs ≤2 cm has been proposed by recent guidelines, but evidence is scarce and limited to single institutional series. In this international cohort study of 263 resected cPanNENs from 16 institutions worldwide, a preoperative size >2 cm was independently associated with aggressive behavior both in the whole cohort and in the subset of asymptomatic patients; notably, only 1 of 61 asymptomatic cPanNENs ≤2 cm was aggressive. Based on these results, a watch-and-wait policy for sporadic asymptomatic cPanNENs ≤2 cm seems justified and safe. The aim of this study was to characterize an international cohort of resected cystic pancreatic neuroendocrine neoplasms (cPanNENs) and identify preoperative predictors of aggressive behavior. The characteristics of cPanNENs are unknown and their clinical management remains unclear. An observational strategy for asymptomatic cPanNENs ≤2 cm has been proposed by recent guidelines, but evidence is scarce and limited to single-institutional series. Resected cPanNENs (1995-2017) from 16 institutions worldwide were included. Solid lesions (>50% solid component), functional tumors, and MEN-1 patients were excluded. Aggressiveness was defined as lymph node (LN) involvement, G3 grading, distant metastases, and/or recurrence. Overall, 263 resected cPanNENs were included, among which 177 (63.5%) were >2 cm preoperatively. A preoperative diagnosis of cPanNEN was established in 162 cases (61.6%) and was more frequent when patients underwent endoscopic ultrasound [EUS, odds ratio (OR) 2.69, 95% confidence interval (CI) 1.52-4.77] and somatostatin-receptor imaging (OR 3.681, 95% CI 1.809-7.490), and for those managed in specialized institutions (OR 3.12, 95% CI 1.57-6.21). Forty-one cPanNENs (15.6%) were considered aggressive. In the whole cohort, LN involvement on imaging, age >65 years, preoperative size >2 cm, and pancreatic duct dilation were independently associated with aggressive behavior. In asymptomatic patients, older age and a preoperative size >2 cm remained independently associated with aggressiveness. Only 1 of 61 asymptomatic cPanNENs ≤2 cm displayed an aggressive behavior. The diagnostic accuracy of cPanNENs is increased by the use of EUS and somatostatin-receptor imaging and is higher in specialized institutions. Preoperative size >2 cm is independently associated with aggressive behavior. Consequently, a watch-and-wait policy for sporadic asymptomatic cPanNENs ≤2 cm seems justified and safe for most patients.
doi: https://doi.org/10.1097/SLA.0000000000003508
- Long non-coding RNA PTTG3P functions as an oncogene by sponging miR-383 and up-regulating CCND1 and PARP2 in hepatocellular carcinoma
BMC cancer 2019 Jul;19(1):731
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31340767
BACKGROUND: Emerging evidence indicates that Long non-coding RNAs (LncRNAs) and microRNAs (miRNAs) play crucial roles in tumor progression, including hepatocellular carcinoma (HCC). However, whether there is a crosstalk between LncRNA pituitary tumor-transforming 3 (PTTG3P) and miR-383 in HCC remains unknown. This study is designed to explore the underlying mechanism by which LncRNA PTTG3P sponges miR-383 during HCC progression. METHODS: qPCR and Western blot were used to analyze LncRNA PTTG3P, miR-383 and other target genes’ expression. CCK-8 assay was performed to examine cell proliferation. Annexin V-PE/PI and PI staining were used to analyze cell apoptosis and cell cycle distribution by flow cytometry, respectively. Transwell migration and invasion assays were used to examine cell migration and invasion abilities. An in vivo xenograft study was performed to detect tumor growth. Luciferase reporter assay and RNA pull-down assay were carried out to detect the interaction between miR-383 and LncRNA PTTG3P. RIP was carried out to detect whether PTTG3P and miR-383 were enriched in Ago2-immunoprecipitated complex. RESULTS: In this study, we found that PTTG3P was up-regulated in HCC tissues and cells. Functional experiments demonstrated that knockdown of PTTG3P inhibited cell proliferation, migration and invasion, and promoted cell apoptosis, acting as an oncogene. Mechanistically, PTTG3P upregulated the expression of miR-383 targets Cyclin D1 (CCND1) and poly ADP-ribose polymerase 2 (PARP2) by sponging miR-383, acting as a competing endogenous RNA (ceRNA). The PTTG3P-miR-383-CCND1/PARP2 axis modulated HCC phenotypes. Moreover, PTTG3P also affected the PI3K/Akt signaling pathway. CONCLUSION: The data indicate a novel PTTG3P-miR-383-CCND1/PARP2 axis in HCC tumorigenesis, suggesting that PTTG3P may be used as a potential therapeutic target in HCC.
doi: https://doi.org/10.1186/s12885-019-5936-2
- Age-related morphological changes in the pancreas and their association with pancreatic carcinogenesis
Pathology international 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31339204
Age-related pathological changes in the pancreas have been unclear because they are often minor and nonspecific. However, recent studies have shown that they are closely related to various pathological conditions such as pancreatic cancer and diabetes mellitus. Knowledge of age-related changes is important to determine appropriate prevention, detection, and treatment strategies for various diseases observed in elderly patients. We present a review of the pathological age-related non-neoplastic changes in the exocrine pancreas such as pancreatic fatty replacement, lobulocentric pancreatic atrophy, pancreatic duct ectasia, and metaplasia of exocrine pancreas, as well as changes in islet cells. We have discussed common pancreatic neoplasms in elderly patients, such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMNs), and pancreatic ductal adenocarcinoma (PDAC). Age-related pathological changes play a key role in pancreatic carcinogenesis via telomere dysfunction. Further studies are warranted to clarify molecular mechanisms of pancreatic carcinogenesis in elderly patients.
doi: https://doi.org/10.1111/pin.12837
- Morphologic Factors Predict Pain Relief Following Pancreatic Head Resection in Chronic Pancreatitis Description of the Chronic Pancreatitis Pain Relief (CPPR) Score
Annals of surgery 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31348039
OBJECTIVE: This study analyzes the clinicopathologic findings and their impact on outcome of patients so as to identify which patients benefit most from surgical treatment in chronic pancreatitis, especially in regard to pain relief. SUMMARY BACKGROUND DATA: The predominant symptom of chronic pancreatitis is chronic pain resulting in reduced quality of life. It is well known that the main reason for development of the disease is abuse of alcohol and nicotine, but only little data on factors influencing outcome are available. METHODS: One thousand one hundred forty-six consecutive patients who underwent surgery for chronic pancreatitis were included. Clinicopathologic data, including morphology of the pancreas in preoperative diagnostics and the histopathologic results, were evaluated. A long-term follow-up including Quality of Life and pain scores was performed. Additionally, we describe the novel Chronic Pancreatitis Pain Relief Score (CPPR-Score) as a tool for prediction of pain relief. RESULTS: Overall the rate of pain relief was 79.8% after surgery. The presence of an inflammatory mass in the pancreatic head larger than 4 cm (P < 0.001), presence of a dilated main pancreatic duct of over 4 mm (P < 0.001), histopathologically detected severe calcifications (P = 0.001) and severe fibrosis (P < 0.001) as well as ethanol induced disease (P < 0.001) found to be strong independent prognostic factors for pain relief. The CPPR-Score (0-5 points) proved to be a very good predictive score for pain-relief (P < 0.001). CONCLUSIONS: The rate of pain relief after surgical treatment in chronic pancreatitis is high and the commonly used procedures can be performed with acceptable morbidity and mortality. The Chronic Pancreatitis Pain Relief Score allows identifying patients who will benefit most from surgery.
doi: https://doi.org/10.1097/SLA.0000000000003439
- Acinar cell carcinoma of the pancreas with thyroid-like follicular features: first description of a new diagnostic challenging subtype
Virchows Archiv : an international journal of pathology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31338587
Acinar cell carcinomas (ACCs) of the pancreas are a heterogeneous group of neoplasms showing a wide spectrum of morphological features including acinar, solid, glandular, and trabecular architecture. In addition, uncommon cytological aspects have recently been described and include oncocytic, spindle, clear, and pleomorphic cell types. This wide histological spectrum represents a challenge in the diagnostic task for pathologists. Molecular mechanisms involved in the onset and progression of ACCs are not completely known, but, in general, they differ from those observed in ductal adenocarcinomas or neuroendocrine neoplasms of the pancreas and frequently include alterations in the APC/β-catenin pathway. In the present paper, we describe a new variant of ACC showing thyroid-like follicular features and CTNNB1 mutation. This phenotype needs to be included in the spectrum of morphological presentation of ACC.
doi: https://doi.org/10.1007/s00428-019-02628-3
- Overall survival in patients over 40 years old with surgically resected pancreatic carcinoma: a SEER-based nomogram analysis
BMC cancer 2019 Jul;19(1):726
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31337369
BACKGROUND: The aim of this study was to identify the determinants of overall survival (OS) within patients over 40 years old with surgically resected pancreatic carcinoma (PC), and to develop a nomogram with the intention of OS predicting. METHODS: A total of 6341 patients of 40 years of age or later with surgically resected PC between 2010 and 2015 were enrolled from the Surveillance, Epidemiology, and End Results (SEER) program and randomly assigned into training set (4242 cases) and validation set (2099 cases). A nomogram was constructed for predicting 1-, 2- and 3-years OS based on univairate and multivariate Cox regression. The C-index and calibration plot were adopted to assess the nomogram performance. RESULTS: Our analysis showed that age, location of carcinoma in pancreas, tumor grade, TNM stage, size of carcinoma together with lymph node ratio (LNR) were considered to be independent overall survival predictors. A nomogram based on these six factors was developed with C-index being 0.680 (95%CI: 0.667-0.693). All calibration curves of OS fitted well. The OS curves stratified by nomogram-predicted probability score (≥20, 10-19 and < 10) demonstrated statistically significant difference not only within training set but also in validation set. CONCLUSIONS: The present nomogram for OS predicting can serve as the efficacious survival-predicting model and assist in accurate decision-making for patients over 40 years old with surgically resected PC.
doi: https://doi.org/10.1186/s12885-019-5958-9
- Anticancer immunotherapy by MFAP5 blockade inhibits fibrosis and enhances chemosensitivity in ovarian and pancreatic cancer
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31332047
PURPOSE: Recent studies demonstrate the role of the tumor microenvironment in tumor progression. However, strategies used to overcome the malignant phenotypes of cancer cells modulated by the microenvironment have not been thoroughly explored. In this study, we evaluated the therapeutic efficacy of a newly developed monoclonal antibody targeting microfibril associated protein 5 (MFAP5), which is secreted predominately by CAFs, in ovarian and pancreatic cancer models. EXPERIMENTAL DESIGN: Monoclonal antibodies were developed using human MFAP5 recombinant protein as an antigen in mice and antibodies from hybridoma clones were evaluated for their specificity to human and murine MFAP5. An Octet RED384 system was used to determine the kinetics of binding affinity and the specificity of the antibody clones, which were followed by epitope mapping and functional characterization by in vitro assays. The therapeutic efficacy of a lead anti-MFAP5 antibody clone 130A in tumor suppression was evaluated by ovarian tumor- and pancreatic tumor-bearing mouse models. RESULTS: Three hybridoma clones, which produced antibodies with high affinity and specificity to MFAP5, were selected for functional studies. Antibody clone 130A, which recognizes a common epitope shared between human and murine MFAP5 protein, were further selected for in vivo studies. Results showed that clone 130A down-regulated MFAP5-induced collagen production in CAFs, suppressed intratumoral microvessel leakiness, and enhanced paclitaxel bioavailability in both ovarian and pancreatic cancer mouse models. CONCLUSIONS: These data suggest that MFAP5 blockade using an immunologic approach inhibits fibrosis, induces tumor vessel normalization and enhances chemosensitivity in ovarian and pancreatic cancer, and can be used as a novel therapeutic agent.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0187
- Metastatic low-grade endometrial stromal sarcoma of uterus presenting as a primary pancreatic tumor: case presentation and literature review
Diagnostic pathology 2019 Apr;14(1):30
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31010432
BACKGROUND: Metastatic tumors to the pancreas are uncommon, accounting for approximately 2% of pancreatic malignancies. The most common primary tumors to give rise to pancreatic metastases are carcinomas. CASE PRESENTATION: A 50-year old female patient was investigated for a cause of abdominal discomfort. She had a 2-year history of menorrhagia and dysmenorrhea which was ascribed to a fibroid uterus. On imaging, she was found to have a large solid and cystic mass in the tail of the pancreas. Imaging also confirmed a fibroid uterus. A distal pancreatectomy and splenectomy showed a 9 cm circumscribed mass within, and grossly confined to, the parenchyma of the pancreatic tail. Microscopically, the pancreatic lesion was lobulated, and well-circumscribed, but focally infiltrative. It comprised sheets of uniform spindled to epithelioid cells with round to oval nuclei, coarse to vesicular chromatin, visible nucleoli, nuclear grooves and clear to eosinophilic cytoplasm. Prominent arterioles were identified. The stroma was collagenized in areas. Occasional hemosiderin-laden macrophages were seen, and focal cystic change was present. There was no evidence of nuclear pleomorphism, mitotic activity or necrosis, and there was no evidence of endometriosis despite multiple sections being taken. Immunohistochemistry showed that the tumor cells were positive for CD10, estrogen receptor (ER), progesterone receptor (PR), Wilms tumor-1 (WT-1) and smooth muscle actin (SMA). RNA sequencing detected a PHF1 rearrangement. The morphological, immunohistochemical and molecular features were of a low-grade endometrial stromal sarcoma (LG-ESS). Subsequent total hysterectomy and bilateral salpingo-oophorectomy 3 months later, showed uterine fibroids and a 5 cm low-grade endometrial stromal sarcoma confined to the uterus, with lymphatic invasion. CONCLUSIONS: To the best of our knowledge, this is the first documented case of metastatic endometrial stromal sarcoma of uterus presenting as a primary pancreatic neoplasm. An unexpected extra-uterine location and unusual presentation of ESS may make the diagnosis challenging, despite classic histological features. Morphological, immunohistochemical and molecular findings must be combined to render the correct diagnosis.
doi: https://doi.org/10.1186/s13000-019-0807-3
- [Heterotopic tissue in the gastrointestinal tract]
Der Pathologe 2018 Sep;39(5):402-408
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30105611
Heterotopia of the gastrointestinal tract is a common finding. This is due to the complex embryogenesis and the relative ease to detect heterotopic tissue during endoscopy. The reason for biopsy is mostly to rule out neoplasms or to define specific causes of inflammation. Heterotopic tissue can occur in any location of the gastrointestinal tract. The most frequent are gastric heterotopia, pancreatic heterotopia, and heterotopia of Brunner’s gland. On rare occasions, heterotopic tissue of salivary gland type as well as heterotopias of apocrine glands, thyroid, and prostatic tissue have been described. The most frequently involved organs are the small intestine, in particular the duodenum, the esophagus, and the stomach. Heterotopia of the large bowel occurs exclusively in the rectum. Most heterotopias do not cause symptoms and are easily diagnosed by biopsy and histology. However, depending on location, size, and the kind of underlying heterotopic tissue, they may cause significant complications, such as inflammation, ulceration and perforation, obstruction, intussusception, and severe life-threatening bleeding. Another rare but significant complication is neoplasia. Gastric heterotopias may give rise to pyloric gland adenomas within the bowel or rarely adenocarcinomas of the esophagus. Pancreatic heterotopia can be complicated by ductal type pancreatic adenocarcinomas, by acinus cell carcinomas, by intraductal papillary mucinous neoplasias, and also by endocrine tumors. The present paper summarizes our current knowledge about heterotopias in a topographic clinico-pathological manner.
doi: https://doi.org/10.1007/s00292-018-0466-2
- Higher IL-6 peri-tumoural expression is associated with gastro-intestinal neuroendocrine tumour progression
Pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31466863
An association of well-differentiated gastroenteropancreatic neuroendocrine tumours (WD GEP NETs) with metabolic syndrome (MetS) was recently described. Yet no molecular mechanisms linking the two conditions are known. This study’s aim was to identify putative molecular signatures linking WD GEP NETs and MetS to gain further insight into potential mechanisms for this association. Patients with WD GEP NETs (n=39), pancreatic (panNET) and gastro-intestinal (GI-NET), were clinically evaluated for presence of MetS. WD GEP NETs immunohistochemistry staining for Forkhead box protein M1 (FOXM1), insulin growth factor 1 receptor (IGF1R), Ki-67 and interleukin 6 (IL-6) was performed and quantified by computerised morphometric analysis. FOXM1, Ki-67, IGF1R or IL-6 expression in WD GEP NETs was not influenced by the presence of MetS. IL-6 peritumoural expression was higher in GI-NETs of patients with low HDL cholesterol (0.018±0.005% vs 0.030±0.005%, p=0.02). In GI-NETs, a higher IL-6 expression was also associated with disease progression (0.026±0.004% vs 0.016±0.002%, p=0.03). In WD GEP-NETs, MetS did not influence FOXM1, IGF1R and IL-6 expression. In GI-NETs, IL-6 expression was influenced by the MetS feature low HDL, and positively associated with disease progression. These data suggest that local and systemic inflammatory status can potentially modulate GI-NET behaviour.
doi: https://doi.org/10.1016/j.pathol.2019.07.001
- Modulation of all-trans retinoic acid-induced MiRNA expression in neoplastic cell lines: a systematic review
BMC cancer 2019 Aug;19(1):866
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31470825
BACKGROUND: Cancer is a genetic and epigenetic disease that involves inactivation of tumor suppressor genes and activation of proto-oncogenes. All-trans retinoic acid (ATRA) is an isomer of retinoic acid involved in the onset of differentiation and apoptosis of a number of normal and cancer cells, functioning as an anti-cancer agent in several neoplasms. Ectopic changes in the expression of certain microRNAs (miRNAs) occur in response to ATRA, leading to phenotypic alterations in neoplastic cell lines. Moreover, the modulation of miRNA patterns upon ATRA-treatment may represent an effective chemopreventive and anti-cancer therapy strategy. The present systematic review was performed to provide an overview of the modulation of ATRA-induced miRNA expression in different types of neoplastic cells and identify the efficacy of intervention factors (i.e., concentration and duration of treatment) and how they influence expression profiles of oncogenesis-targeting miRNAs. METHODS: A systematic search was conducted according to the PRISMA statement via the US National Library of Medicine MEDLINE/PubMed bibliographic search engine. RESULTS: The search identified 31 experimental studies involving human cell lines from nine different cancer types (neuroblastoma, acute myeloid leukemia, breast cancer, lung cancer, pancreatic cancer, glioma, glioblastoma, embryonal carcinoma, and colorectal cancer) treated with ATRA at concentrations ranging from 10- 3 μmol/L to 102 μmol mol/L for 24 h to 21 days. CONCLUSION: The concentrations used and the duration of treatment of cancer cells with ATRA varied widely. The presence of ATRA in the culture medium of cancer cells was able to modulate the expression of more than 300 miRNAs, and inhibit invasive behavior and deregulated growth of cancer cells, resulting in total tumor remission in some cases. ATRA may thus be broadly effective for neoplasm treatment and prevention, although these studies may not accurately represent in vivo conditions. Additional studies are required to elucidate ATRA-induced miRNA modulation during neoplasm treatment.
doi: https://doi.org/10.1186/s12885-019-6081-7
- CA19-9 decrease and survival according to platelet level in patients with advanced pancreatic cancer
BMC cancer 2019 Aug;19(1):860
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31470818
BACKGROUND: CA19-9 decrease during treatment has been associated with superior survival of pancreatic cancer in several studies. The evidence to show the correlation of high platelet level with inferior survival is insufficient in pancreatic cancer. It also remains unclear whether the association between CA19-9 decrease and survival was corresponded to different levels of platelet in metastatic pancreatic cancer. METHODS: We measured CA19-9 serum concentration and platelet level at baseline and after the second cycle of chemotherapy for 200 advanced pancreatic cancer patients. A Cox proportional hazards model was used to compute mortality hazard ratios (HRs) for CA19-9 decrease, adjusting for potential confounders, including age, sex, KPS, prediagnosis body mass index, Diabetes Mellitus, tumor location, first-line chemotherapy regimen, and radiotherapy. RESULTS: We found that the association of CA19-9 decrease with superior overall survival was stronger in advanced pancreatic cancer with a low level of platelet (Pinteraction < 0.001) compared with intermediate and high level of platelet. Multivariable-adjusted hazard ratios per unit decrease of CA19-9 change was 0.45 [95% confidence interval (CI), 0.33 to 0.62] in cases with low platelet level, 0.74 (95% CI, 0.50 to 1.09) in cases with intermediate platelet level, and 0.94 (95% CI, 0.74 to 1.10) in cases with high platelet level. A similar differential association was found between CA19-9 decrease and progression-free survival in strata of platelet level (Pinteraction = 0.034). CONCLUSION: The association of CA19-9 decrease with superior pancreatic cancer survival appeared to be pronounced in patients with a low platelet level. This finding could provide supports for the underlying mechanisms of CA19-9 involved in platelet / tumor cell interaction.
doi: https://doi.org/10.1186/s12885-019-6078-2
- Acute Pancreatitis Associated With Myotonic Dystrophy Type I
Pancreas 2019 Sep;48(8):e63-e64
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425487
doi: https://doi.org/10.1097/MPA.0000000000001366
- Minimally Invasive Treatment for Severe Acute Pancreatitis With Superior Mesenteric Vein and Common Bile Duct Stenosis: A Case Report and Review of the Literature
Pancreas 2019 Sep;48(8):e61-e63
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425486
doi: https://doi.org/10.1097/MPA.0000000000001379
- Clinical Utility of Cytokine Biomarker Analysis of Pancreatic Cyst Fluid Obtained by Endoscopic Ultrasound Fine Needle Aspiration: A Pilot Study
Pancreas 2019 Sep;48(8):e60-e61
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425485
doi: https://doi.org/10.1097/MPA.0000000000001365
- Cigarette Smoking and Mortality in Patients With Pancreatic Cancer: A Systematic Review and Meta-analysis
Pancreas 2019 Sep;48(8):985-995
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425484
Current evidence on cigarette smoking associated with pancreatic cancer mortality is limited. We searched MEDLINE, Web of Science, and Embase databases to identify relevant studies published through January 31, 2018. A random-effects model was used to estimate summary hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 20 studies were retrieved, involving 2,517,623 participants. Of these, more than 15,341 patients with pancreatic cancer died. Compared with never smokers, current (summary HR, 1.56; 95% CI, 1.34-1.83) and former (summary HR, 1.15; 95% CI, 1.06-1.26) smokers had elevated risk of total mortality in patients diagnosed with pancreatic cancer. This effect of cigarette smoking is observed both in the Western regions and the Asia-Pacific regions. This effect of smoking is independent of alcohol use, body mass index, and history of diabetes but is modified by tumor stage and study settings. Dose-response associations between smoking and pancreatic cancer mortality were revealed for smoking intensity, cumulative amount of cigarettes smoked, and duration of smoking. Cigarette smoking was associated with an increase in total mortality for patients with pancreatic cancer. Future studies should further clarify the role of smoking as an effect modifier in treatment trials of pancreatic cancer.
doi: https://doi.org/10.1097/MPA.0000000000001383
- A Qualitative Review of Neoadjuvant Chemotherapy in Resectable Pancreatic Adenocarcinoma
Pancreas 2019 Sep;48(8):973-984
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425483
The aim of this study was to evaluate outcomes of patients with resectable pancreatic adenocarcinoma (PDAC) who underwent neoadjuvant chemotherapy. The MEDLINE and PubMed databases were searched to identify relevant original articles investigating neoadjuvant therapy in resectable PDAC. Qualitative analyses were performed to investigate patient selection, disease stage, impact on perioperative outcomes, and cost-effectiveness. Forty-three studies met inclusion criteria for this review. Neoadjuvant chemotherapy for upfront resectable PDAC is cost-effective, safe, may result in lower stage disease and has potential survival advantages. With proper patient selection, neoadjuvant chemotherapy is an appropriate approach for upfront resectable PDAC. Nevertheless, the risk for disease progression and losing a curative surgical window highlights the need for appropriate patient identification, further discovery of superior biomarkers or molecular profiles representative of positive treatment response, and additional prospective comparative study.
doi: https://doi.org/10.1097/MPA.0000000000001376
- Management of Diarrhea in Patients With Carcinoid Syndrome
Pancreas 2019 Sep;48(8):961-972
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425482
Neuroendocrine tumors (NETs) arise from enterochromaffin cells found in neuroendocrine tissues, with most occurring in the gastrointestinal tract. The global incidence of NETs has increased in the past 15 years, likely due to better diagnostic methods. Small-bowel NETs are frequently associated with carcinoid syndrome (CS). Carcinoid syndrome diarrhea occurs in 80% of CS patients and poses a substantial symptomatic and economic burden. Patients with CS diarrhea frequently suffer from diarrhea and flushing and report corresponding impairment in quality of life, requiring substantial changes in daily activities and lifestyle. Treatment paradigms range from surgical debulking to liver-directed therapies to treatment with somatostatin analogs, nonspecific anti-diarrheal agents, and a tryptophan hydroxylase inhibitor. Other causes of diarrhea, including steatorrhea, short bowel syndrome, and bile acid malabsorption, should be considered in NET patients with refractory diarrhea. More therapeutic options are needed for symptomatic management of patients with NETs, and better understanding of the pathophysiology can empower clinicians with improved patient care.
doi: https://doi.org/10.1097/MPA.0000000000001384
- Inflammation Promotes Progression of Pancreatic Cancer Through WNT/��-Catenin Pathway-Dependent Manner
Pancreas 2019 Sep;48(8):1003-1014
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404031
OBJECTIVE: Identify the molecular mechanism of inflammatory stimuli induced pancreatic cancer progression. METHODS: RNA-seq, microarray assay and bioinformatics analyses were used to identify differentially expressed genes. Immunohistochemical staining was performed to evaluate CD68, CD163, β-catenin, CD103, CCL3 markers. Quantitative real-time polymerase chain reaction (qRT-PCR), luciferase reporter assay, apoptosis assay, wound healing assay and immunofluorescence were performed to study the relationship of inflammatory stimuli and WNT/β-catenin pathway. RESULTS: Differentially expressed genes of macrophage-conditioned medium-treated pancreatic cancer cells were related with WNT/β-catenin pathway. Inflammatory stimuli could activate WNT/β-catenin signaling pathway. In 106 pancreatic cancer patients, nuclear β-catenin expression of CD68-high group was much higher than CD68-low group (P < 0.05), as same as CD163 (P < 0.05). Inflammatory stimuli downregulated the expression of CCL3 via WNT/β-catenin pathway and inhibited the chemotaxis of CD103 dendritic cells. Six pancreatic cancer prognosis associating genes were upregulated by inflammatory stimuli via WNT/β-catenin pathway. Transforming growth factor-β promoted malignant biological behavior of pancreatic cancer cells through WNT/β-catenin pathway-dependent mechanism. CONCLUSIONS: Our present study provided a novel mechanism involved in the inflammation-driven cancer progression through tumor immune escape and downstream gene regulation of WNT/β-catenin pathway-dependent manner.
doi: https://doi.org/10.1097/MPA.0000000000001386
- Detection of Reg3�� by Immunohistochemistry in Cerulein-Induced Model of Acute Pancreatic Injury in Mice and Rats
Pancreas 2019 Sep;48(8):1015-1025
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404030
OBJECTIVE: In a continuation of previous work, Reg3γ protein was further evaluated as a biomarker of pancreatic injury using immunohistochemistry in an additional species. METHODS: Mice and rats were treated with intraperitoneal cerulein injections, creating acute pancreatic injury. Mice received 2, 4, or 6 doses, and rats received 1, 2, or 3 doses of cerulein creating low, medium, and high treatment groups. Control animals were dosed with phosphate-buffered saline at corresponding volumes and intervals. Groups of 6 animals were killed 1, 3, 6, 24, and 48 hours after final treatments. Reg3γ immunohistochemical staining and image analysis were performed on pancreatic tissue obtained 6, 24, or 48 hours after control or cerulein treatment. Staining was quantified using image analysis software to calculate area of positivity as a percentage of total tissue area. RESULTS: Percent positivity of Reg3γ in both species rose by 6 hours, peaked by 24 hours across all 3 cerulein doses, and dropped significantly by 48 hours. In high-dose rats with accompanying gene expression data, Reg3γ gene expression corresponded temporally with quantitative staining data. CONCLUSIONS: Reg3γ staining quantified through image analysis showed a time- and dose-response in cerulein-treated mice and rats.
doi: https://doi.org/10.1097/MPA.0000000000001382
- Pancreatic Function in Chronic Pancreatitis: A Cohort Study Comparing 3 Methods of Detecting Fat Malabsorption and the Impact of Short-term Pancreatic Enzyme Replacement Therapy
Pancreas 2019 Sep;48(8):1068-1078
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404029
OBJECTIVES: Reliable pancreatic function tests in patients with chronic pancreatitis (CP) are needed. This cohort study identified malabsorption in people with CP compared with healthy people and then investigated short-term pancreatic enzyme replacement therapy (PERT) and fat malabsorption, nutritional status, and quality of life (QOL). METHODS: Subjects with CP were evaluated before and after PERT and compared with the healthy cohort using coefficient of fat absorption (CFA), stool bomb calorimetry, and the malabsorption blood test (MBT). Anthropometrics, micronutrients, and QOL data were collected. Group means at baseline and after PERT were analyzed. RESULTS: The 24 subjects with CP had greater stool energy loss (5668 cal/g [standard deviation {SD}, 753] vs 5152 cal/g [SD, 418], P < 0.01), reduced triglyceride absorption (MBT, 8.3 mg·h/dL [SD, 4.3] vs 17.7 mg·h/dL [SD, 10.3], P < 0.001), lower fat intake, and poorer QOL. Differences in CFA were not significant (90.9% [SD, 12.8] vs 95.4% [SD, 9.3]). After PERT, triglyceride absorption (Δ = 1.7 [SD, 3], P < 0.05) and QOL increased. CONCLUSIONS: The MBT detected changes in triglyceride absorption in the absence of CFA changes. The MBT may be helpful in guiding PERT initiation in patients with CP before significant morbidity.
doi: https://doi.org/10.1097/MPA.0000000000001381
- Risk and Outcomes of Clostridium difficile Infection With Chronic Pancreatitis
Pancreas 2019 Sep;48(8):1041-1049
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404028
OBJECTIVES: Chronic pancreatitis (CP) is associated with high rates of recurrent hospitalizations, which predisposes to Clostridium difficile infection (CDI). We investigate the burden of CDI in CP. METHODS: We identified records of patients with CP from the Nationwide Inpatient Sample (NIS) 2012-2014 and estimated the impact of CDI on their outcomes. We calculated the adjusted odds ratio (AOR) of CP on having CDI (NIS 2014). From NIS 2007-2014, we plotted the trends of CDI and its interaction with CP. RESULTS: From 2012 to 2014, 886 (2.72%) of the 32,614 CP patients had concomitant CDI, which was associated with poorer outcomes: acute kidney injury (AOR, 2.57 [95% confidence interval {CI}, 2.11-3.13]), length of stay (13.3 vs 7.4 days), and charges (US $127,496 vs US $72,767), but not mortality (AOR, 0.93 [95% CI, 0.28-3.05]). In 2014, CP was associated with an increased risk of CDI (crude odds ratio, 2.10 [95% CI, 1.95-2.26]), which persisted after multivariate adjustment (AOR, 2.03 [95% CI, 1.87-2.19]). From 2007 to 2014, the annual prevalence of CDI was 106.4 cases per 10,000 hospitalizations, increasing from 2007 (95.5/10,000) to 2014 (118.4/10,000), with a 3.7 times higher annual rate of increase among CP versus no-CP patients (13.4/10,000 vs 3.7/10,000 population/year). CONCLUSIONS: Chronic pancreatitis patients have high burden of CDI and may benefit from CDI prophylaxis.
doi: https://doi.org/10.1097/MPA.0000000000001380
- Microbial Contamination, Infection, and Antimicrobial Use During Total Pancreatectomy With Islet Autotransplantation
Pancreas 2019 Sep;48(8):1050-1055
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404027
OBJECTIVES: Total pancreatectomy with islet autotransplantation can relieve pain associated with chronic pancreatitis while preserving islet function. Islet preparations are often contaminated by enteric flora. We assessed the impact of contaminated islet preparations on the prevalence of postoperative infection. METHODS: Electronic health records for patients who underwent total pancreatectomy with islet autotransplantation from August 1, 2011, to November 15, 2017 were retrospectively reviewed to compare the prevalence of postoperative infection in patients with a positive islet culture and islet culture negative patients. RESULTS: Sixty-one patients were included. Twenty-nine patients (47.5%) had a positive islet culture, and 23 (79.3%) of these patients received antimicrobial prophylaxis. The prevalence of postoperative infection did not differ between the islet culture positive and islet culture negative groups (41% vs 34%, P = 0.57). No infections occurred in the 6 islet culture positive patients who did not receive prophylaxis. No difference in intensive care unit or hospital length of stay or in 30-day or 90-day readmission rates were observed. CONCLUSIONS: Despite the common use of postoperative systemic antimicrobials, we observed no difference in the prevalence of postoperative infection, length of stay, or hospital readmission in patients receiving a contaminated islet preparation. If prophylactic antimicrobials are used, the duration should be minimized.
doi: https://doi.org/10.1097/MPA.0000000000001378
- Association Between Pancreatic Cystic Lesions and High-grade Intraepithelial Neoplasia and Aging: An Autopsy Study
Pancreas 2019 Sep;48(8):1079-1085
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404026
OBJECTIVES: This study aimed to clarify clinicopathological features of pancreatic cysts. METHODS: Pancreata from 280 autopsies (median, 83 years; male, 146; female, 134) were sectioned every 5 mm. Cysts (<10 mm) were diagnosed as a simple cyst or low-grade, intermediate-grade, or high-grade dysplasia. RESULTS: We found 236 cysts in 93 patients (33.2%). The number and diameter of cysts increased according to the age. Of the 236 cysts, 9 (3.8%) were with high-grade dysplasia. Cysts with high-grade dysplasia arose in the pancreata of older patients with larger numbers of cysts. In contrast, 15 noncystic lesions with high-grade dysplasia were also detected. Hence, in total, 24 high-grade dysplastic lesions in 15 patients (5.4%) were noted. Of the 15 patients with high-grade dysplastic lesions, in 10 patients, the condition was accompanied by pancreatic cysts, whereas 5 patients did not have any cysts in the pancreas; therefore, patients with cyst showed higher incidence of high-grade dysplasia (10.8%; P = 0.0047) than patients without cyst (2.7%). All cysts with high-grade dysplasia were located in the branch duct of the pancreatic head/body, whereas 20% of noncystic lesions with high-grade dysplasia were located in the main pancreatic duct. CONCLUSIONS: Cystic lesions with high-grade dysplasia may have different characteristics compared with noncystic high-grade dysplasia.
doi: https://doi.org/10.1097/MPA.0000000000001374
- 18F-Fluorodeoxyglucose Positron Emission Tomography Predicts Treatment Efficacy and Clinical Outcome for Patients With Pancreatic Carcinoma: A Meta-analysis
Pancreas 2019 Sep;48(8):996-1002
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404025
OBJECTIVES: F-Fluorodeoxyglucose positron emission tomography (FDG-PET) has been an important modality for detecting malignancies. Recently, an increasing number of studies reported the utility of FDG-PET parameters in predicting clinical outcomes and treatment assessment in variety of cancers. We aimed at clarifying both the prognostic role and assessment value of FDG-PET in pancreatic carcinoma. METHODS: We systematically searched electronic databases of PubMed, Embase, Cochrane Library, and Web of Science to identify relevant studies to conduct this meta-analysis. Comparative analyses of the pooled hazard ratio (HR) for overall survival were performed to assess the utility of FDG-PET parameters in prognosis evaluation and treatment assessment by random-effect model. RESULTS: Twenty-three studies with 1762 patients met the inclusion criteria of this meta-analysis. The pooled results revealed that greater maximum standardized uptake value of the primary tumor was significantly correlated with poorer overall survival (HR, 1.31; 95% confidence interval, 1.15-1.50; P < 0.001). Besides, greater reduction of maximum standardized uptake value after treatments indicated significant better overall survival (HR, 0.68; 95% confidence interval, 0.47-0.98; P = 0.037). CONCLUSIONS: F-Fluorodeoxyglucose positron emission tomography parameters might be helpful not only for predicting survival outcome but also for selecting potentially efficacious treatments in patients with pancreatic carcinoma.
doi: https://doi.org/10.1097/MPA.0000000000001375
- Time to Adjuvant Systemic Therapy Following Pancreatic Cancer Resection and Effect on Outcome
Pancreas 2019 Sep;48(8):1086-1091
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404024
OBJECTIVES: The appropriate timing of chemotherapy following surgery for resectable pancreatic adenocarcinoma is controversial. Using the National Cancer Database we evaluated time to initiation of chemotherapy postresection and correlated with outcome. METHODS: We identified stage I-III pancreatic adenocarcinoma treated surgically with adjuvant chemoradiotherapy. Receiver operator curve analysis identified an interval of 66 days as the a priori value for largest discrepancy in outcome. Multivariable logistic regression analysis identified variables associated with increased time to chemotherapy postoperatively (>66 days). Propensity matching was performed to account for indication bias. RESULTS: In total, 6873 and 3348 patients received chemotherapy before and after the 66-day cutoff, respectively. Predictors of expedited chemotherapy included lower comorbidity, treatment outside a community program in an urban location, having insurance, white race, and treatment after 2009. Propensity-matched median survival was 21.8 months for all patients, and of these, 6462 were stage 1. Five-year survival was 20% in patients receiving chemotherapy within 66 days and 18% in those not (P = 0.0266). In stage 1 patients, 5-year survival was 23% versus 21% (P = 0.0116) in favor of expedited chemotherapy. CONCLUSIONS: The present propensity-matched analysis showed a significant association with survival for earlier delivery of chemotherapy in the adjuvant setting.
doi: https://doi.org/10.1097/MPA.0000000000001373
- Pancreatic Fluid Interleukin-1�� Complements Prostaglandin E2 and Serum Carbohydrate Antigen 19-9 in Prediction of Intraductal Papillary Mucinous Neoplasm Dysplasia
Pancreas 2019 Sep;48(8):1026-1031
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404023
OBJECTIVES: We sought to determine if interleukin (IL)-1β and prostaglandin E2 (PGE2) (inflammatory mediators in pancreatic fluid) together with serum carbohydrate antigen (CA) 19-9 could better predict intraductal papillary mucinous neoplasm (IPMN) dysplasia than individual biomarkers alone. METHODS: Pancreatic cyst fluid (n = 92) collected via endoscopy or surgery (2003-2016) was analyzed for PGE2 and IL-1β (enzyme-linked immunosorbent assay). Patients had surgical pathology-proven IPMN. Threshold values (PGE2 [>1100 pg/mL], IL-1β [>20 pg/mL], and serum CA 19-9 [>36 U/mL]) were determined. RESULTS: Levels of IL-1β were higher in high-grade dysplasia (HGD)/invasive-IPMN (n = 42) compared with low/moderate IPMN (n = 37) (median [range], 54.6 [0-2671] vs 5.9 [0-797] pg/mL; P < 0.001; area under curve [AUC], 0.766). Similarly, PGE2 was higher in HGD/invasive IPMN (n = 45) compared with low/moderate IPMN (n = 47) (median [range], 1790 [20-15,180] vs. 140 [10-14,630] pg/mL; P < 0.001; AUC, 0.748). Presence of elevated PGE2 and IL-1β (AUC, 0.789) provided 89% specificity and 82% positive predictive value (PPV) for HGD/invasive IPMN. Elevated levels of all 3 provided 100% specificity and PPV for HGD/invasive IPMN. CONCLUSIONS: Cyst fluid PGE2, IL-1β, and serum CA 19-9 in combination optimize specificity and PPV for HGD/invasive IPMN and may help build a panel of markers to predict IPMN dysplasia.
doi: https://doi.org/10.1097/MPA.0000000000001377
- Etiologic Distribution of Pancreatic Cystic Lesions Identified on Computed Tomography/Magnetic Resonance Imaging
Pancreas 2019 Sep;48(8):1092-1097
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404022
OBJECTIVES: This study aimed to determine the distribution of etiology of pancreatic cysts using established criteria/markers from cyst fluid analysis and cytology that have been reported to have high specificity in published literature. METHODS: A retrospective study of pancreatic cysts using an endoscopic database from March 2002 and May 2013 was conducted. Pancreatic cysts <10 mm and cysts with a history of pancreatic cancer were excluded. RESULTS: In our cohort of 758 patients with pancreatic cyst(s), the cyst etiology was as follows: mucinous cyst/side-branch intraductal papillary mucinous neoplasms (SB-IPMNs)/mucinous cystic neoplasms (MCN; 48.2%), pseudocyst (27.6%), serous cystadenoma (11%), simple cysts (6.4%), mucinous cystadenocarcinoma (5.1%), and other (1%). Approximately 41% (n = 310) of the cysts were ≥3 cm in size and included the following: pseudocyst (39.7%), mucinous cysts/SB-IPMN/MCN (28.1%), serous cystadenoma (16.7%), mucinous cyst adenocarcinoma (9.7%), and simple cyst (4.8%). In 118 patients with a known history of acute pancreatitis, the cyst diagnoses included pseudocyst (68.7%), mucinous cyst/SB-IPMN/MCN (18.6%), benign/simple cyst (7.6%), and mucinous cystadenocarcinoma (2.5%). CONCLUSIONS: In patients with cystic pancreatic lesion noted on cross-sectional imaging, approximately half of the patients have lesions without malignancy or malignant potential and therefore not requiring surveillance. Endoscopic ultrasound/endoscopic ultrasound-guided fine-needle aspiration evaluation of the pancreatic cysts can help optimize their further management.
doi: https://doi.org/10.1097/MPA.0000000000001372
- Mutational Patterns in Pancreatic Juice of Intraductal Papillary Mucinous Neoplasms and Concomitant Pancreatic Cancer
Pancreas 2019 Sep;48(8):1032-1040
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404021
OBJECTIVES: The aims of this study were to identify genetic characteristics of intraductal papillary mucinous neoplasm (IPMN)-associated pancreatic ductal carcinoma (PDC) and to detect these markers using pancreatic juice. METHODS: From 76 cases, 102 tissues were obtained: 29 cases were noninvasive IPMN, 18 were PDC derived from IPMN (D-PDC; noninvasive part, n = 16; invasive part, n = 18), and 29 were PDC concomitant with IPMN (C-PDC; IPMN part, n = 10; PDC part, n = 29). Moreover, pancreatic juice samples from 28 cases were obtained (noninvasive IPMN, n = 13; D-PDC, n = 7; C-PDC, n = 8). Fifty-one cancer-related genes were analyzed by next-generation sequencing. RESULTS: TP53 mutation rates in D-PDC, C-PDC, and noninvasive IPMN were 67%, 66%, and 10%, respectively. Moreover, KRAS mutational patterns between 2 simultaneous tumors differed in 1 (6.3%) of the 16 D-PDC cases and in 8 (80%) of the 10 C-PDC cases (P = 0.0006). TP53 or multiple KRAS mutations were detected using pancreatic juice more frequently in C-PDC cases than in noninvasive IPMN cases (75% and 23%, respectively, P = 0.03). CONCLUSIONS: Multiple KRAS mutations along with TP53 mutation are genetic markers for C-PDC, which could be detected using pancreatic juice preoperatively.
doi: https://doi.org/10.1097/MPA.0000000000001371
- SpHincterotomy for Acute Recurrent Pancreatitis Randomized Trial: Rationale, Methodology, and Potential Implications
Pancreas 2019 Sep;48(8):1061-1067
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404020
OBJECTIVES: In patients with acute recurrent pancreatitis (ARP), pancreas divisum, and no other etiologic factors, endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla endoscopic sphincterotomy (miES) is often performed to enlarge the minor papillary orifice, based on limited data. The aims of this study are to describe the rationale and methodology of a sham-controlled clinical trial designed to test the hypothesis that miES reduces the risk of acute pancreatitis. METHODS: The SpHincterotomy for Acute Recurrent Pancreatitis (SHARP) trial is a multicenter, international, sham-controlled, randomized trial comparing endoscopic ultrasound + ERCP with miES versus endoscopic ultrasound + sham for the management of ARP. A total of 234 consented patients having 2 or more discrete episodes of acute pancreatitis, pancreas divisum confirmed by magnetic resonance cholangiopancreatography, and no other clear etiology for acute pancreatitis will be randomized. Both cohorts will be followed for a minimum of 6 months and a maximum of 48 months. RESULTS: The trial is powered to detect a 33% risk reduction of acute pancreatitis frequency. CONCLUSIONS: The SHARP trial will determine whether ERCP with miES benefits patients with idiopathic ARP and pancreas divisum. Trial planning has informed the importance of blinded outcome assessors and long-term follow-up.
doi: https://doi.org/10.1097/MPA.0000000000001370
- Expression of Monocarboxylate Transporter 1 Is Associated With Better Prognosis and Reduced Nodal Metastasis in Pancreatic Ductal Adenocarcinoma
Pancreas 2019 Sep;48(8):1102-1110
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404019
OBJECTIVES: Because lactate is believed to support tumor growth, monocarboxylate transporters (MCTs), which transport lactate, have been investigated in multiple tumors. However, the significance of MCTs in pancreatic cancer is unclear. METHODS: A retrospective survey was conducted on 240 patients who underwent surgical resection for pancreatic ductal adenocarcinoma without preoperative treatment. The expression of MCT1, MCT2, MCT3, MCT4, and the glucose transporter 1 (GLUT1) was assessed in tumor cells and cancer-associated fibroblasts (CAFs) by tissue microarrays and immunohistochemistry. The impact of their expression on patient outcome and clinicopathological characteristics was also analyzed. RESULTS: In tumor cells, MCT1, MCT2, MCT3, MCT4, and GLUT1 were detected in 52 (22%), 31 (13%), 149 (62%), 204 (85%), and 235 (98%) cases, respectively. In CAFs, MCT2, MCT4, and GLUT1 were detected in 9 (3.8%), 178 (74%), and 36 (15%) cases, respectively. In tumor cells, MCT1 expression was associated with extended overall and progression-free survival and decreased nodal metastasis. Conversely, MCT4 expression in CAFs was associated with shortened survival. CONCLUSIONS: In tumor cells, MCT1 expression is associated with better prognosis and reduced nodal metastasis in pancreatic cancer, contrary to findings of past in vitro studies. Conversely, MCT4 expression in CAFs is indicative of worse prognosis.
doi: https://doi.org/10.1097/MPA.0000000000001369
- Prevention of Infectious Complications in Acute Pancreatitis: Results of a Single-Center, Randomized, Controlled Trial
Pancreas 2019 Sep;48(8):1056-1060
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404018
OBJECTIVES: This study aimed to investigate the efficiency of imipenem to prevent infectious complications in predicted severe acute pancreatitis (AP). METHODS: Consecutive AP patients were randomized to imipenem 3 × 500 mg intravenously daily or an identical placebo. Exclusion criteria were prior AP, chronic pancreatitis, active malignancy, immune deficiency, active infection, concomitant antibiotic treatment, pregnancy, and patients younger than 18 years. Infectious complications including infected pancreatic necrosis, pneumonia, urinary tract infection, positive blood cultures, sepsis, and other infections were assessed as the primary outcome. Secondary outcomes included mortality, persistent organ failure, systemic inflammatory response syndrome, local complications, serious adverse events, and need for surgical intervention. RESULTS: Forty-nine patients were randomized to each group. Infectious complications were present in 10 versus 12 of 49 patients (relative risk [RR], 0.833; 95% confidence interval [CI], 0.398-1.747). There were no significant differences in infected pancreatic necrosis (RR, 1.5; 95% CI, 0.262-8.588), pneumonia (RR, 1.5; 95% CI, 0.262-8.588), urinary tract infection (RR, 0.6; 95% CI, 0.152-2.374), positive blood cultures (RR, 0.5; 95% CI, 0.047-5.336), sepsis (RR, 0.333; 95% CI, 0.036-3.095), and other (RR, 1.333; 95% CI, 0.315-5.648). We found no significant differences in secondary outcomes. CONCLUSIONS: Concordantly to available evidence, there is currently no ground to support prophylactic use of antibiotics in predicted severe AP.
doi: https://doi.org/10.1097/MPA.0000000000001368
- Defining Pancreatitis as a Risk Factor for Pancreatic Cancer: The Role, Incidence, and Timeline of Development
Pancreas 2019 Sep;48(8):1098-1101
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31404017
OBJECTIVES: Acute and/or chronic pancreatitis has been implicated as an important risk factor for pancreatic cancer; however, the incidence and temporal relationship of pancreatitis before pancreatic cancer diagnosis are unclear. We aim to understand the role and incidence of pancreatitis temporally with the development of pancreatic cancer. METHODS: A population-based study was used to investigate a temporal relationship between pancreatitis and pancreatic cancer diagnoses. Intervals of 3, 6, 12, 24, and 36 months were developed. Demographical data including age, sex, and race were also recorded and analyzed. RESULTS: A total of 50,080 patients were found to have a diagnosis of pancreatic cancer, of which 7420 (14.8%) had prior diagnoses of pancreatitis. Of those, 92% were between the ages of 40 and 89 years. African Americans had a higher rate of pancreatitis before cancer diagnosis when compared with whites (21.2% vs 14.8%, P < 0.0001). Further analysis revealed that pancreatitis occurred in 81.3% of patients 3 months before a diagnosis of pancreas cancer and 98.9% had established diagnoses of pancreatic cancer within 3 years. CONCLUSIONS: Screening of patients older than 40 years who have pancreatitis and unclear etiology of pancreatitis may be warranted, especially in African Americans and male individuals.
doi: https://doi.org/10.1097/MPA.0000000000001367
- The harms of early cessation of trials on systematic reviews - Authors’ reply
The lancet. Gastroenterology & hepatology 2019 Sep;4(9):667-668
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31387729
doi: https://doi.org/10.1016/S2468-1253(19)30228-6
- Silibinin inhibited autophagy and mitochondrial apoptosis in pancreatic carcinoma by activating JNK/SAPK signaling
Pathology, research and practice 2019 Sep;215(9):152530
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31351801
BACKGROUND: Previous investigation have indicated Silibinin induces apoptosis and JNK/SAPK in human pancreatic cancer cells. This study aims to evaluate the further mechanism of Silibinin in pancreatic cancer treatment. MATERIALS AND METHODS: Human pancreatic cancer cell lines SW1990 was treated with Silibinin and/or JNK/SAPK inhibitor SP600125 followed by measurement of cell viability, apoptosis, autophagy, ROS and ATP, and western blotting. RESULTS: Silibinin promoted cell viability and promoted cell apoptosis. The expression of ROS and ATP associated with mitochondrial function was also promoted by the treatment of silibinin. Silibinin also promoted autophagy in pancreatic cancer cells. All these biological effects of Silibinin can be reversed by JNK/SAPK inhibitor. CONCLUSIONS: The biological effects regulated by Silibinin can be mediated by JNK/SAPK signaling. This provides a solid theoretical basis for the role of Silibinin in the treatment of pancreatic cancer.
doi: https://doi.org/10.1016/j.prp.2019.152530
- Tumor Budding in Intrahepatic Cholangiocarcinoma: A Predictor of Postsurgery Outcomes
The American journal of surgical pathology 2019 Sep;43(9):1180-1190
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31335353
Intrahepatic cholangiocarcinoma (ICC) is an extremely aggressive carcinoma. Useful predictors for the patients’ prognosis after surgery have not been fully established. From the University of Tokyo Hospital pathology archives, we reviewed 107 cases of ICC, 54 cases of perihilar cholangiocarcinoma, and 40 cases of extrahepatic cholangiocarcinoma (ECC); we also investigated the significance of tumor budding in ICC, in comparison with perihilar cholangiocarcinoma and ECC. The tumor-budding frequencies were different by tumor location: 40.2% (43/107) in ICC, 70.4% (38/54) in perihilar cholangiocarcinoma, and 60.0% (24/40) in ECC. Tumor budding in ICC was associated with many pathologic indicators associated with invasion, such as major vascular invasion (P=0.012) and Union for International Cancer Control stage (P=0.007). Univariate and multivariate Cox regression analyses revealed tumor budding as a powerful prognostic factor for both recurrence-free survival (RFS) and overall survival (OS) in ICC by univariate (RFS: hazard ratio [HR]: 2.666; 95% confidence interval [CI]: 1.517-4.683, OS: HR: 4.206; 95% CI: 2.447-7.230) and by multivariate analyses (RFS: HR: 3.038; 95% CI: 1.591-5.973, OS: HR: 4.547, 95% CI: 2.348-8.805). Tumor budding was also a significant prognostic factor of perihilar cholangiocarcinoma, but not of ECC. When ICC was divided into 2 subtypes, type 1 (hilar) and type 2 (peripheral), tumor budding was the strong prognostic factor in type 2 ICC, but not in type 1 ICC, suggesting that some differences in biological behavior exist between type 1 ICC and perihilar cholangiocarcinoma. Tumor budding is prognostically important in ICC, and its pathogenetic role in biliary tract carcinomas might be different by anatomic location.
doi: https://doi.org/10.1097/PAS.0000000000001332
- Survival Outcomes Associated With Clinical and Pathological Response Following Neoadjuvant FOLFIRINOX or Gemcitabine/Nab-Paclitaxel Chemotherapy in Resected Pancreatic Cancer
Annals of surgery 2019 Sep;270(3):400-413
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31283563
OBJECTIVE: To compare the survival outcomes associated with clinical and pathological response in pancreatic ductal adenocarcinoma (PDAC) patients receiving neoadjuvant chemotherapy (NAC) with FOLFIRINOX (FLX) or gemcitabine/nab-paclitaxel (GNP) followed by curative-intent pancreatectomy. BACKGROUND: Newer multiagent NAC regimens have resulted in improved clinical and pathological responses in PDAC; however, the effects of these responses on survival outcomes remain unknown. METHODS: Clinicopathological and survival data of PDAC patients treated at 7 academic medical centers were analyzed. Primary outcomes were overall survival (OS), local recurrence-free survival (L-RFS), and metastasis-free survival (MFS) associated with biochemical (CA 19-9 decrease ≥50% vs <50%) and pathological response (complete, pCR; partial, pPR or limited, pLR) following NAC. RESULTS: Of 274 included patients, 46.4% were borderline resectable, 25.5% locally advanced, and 83.2% had pancreatic head/neck tumors. Vein resection was performed in 34.7% and 30-day mortality was 2.2%. R0 and pCR rates were 82.5% and 6%, respectively. Median, 3-year, and 5-year OS were 32 months, 46.3%, and 30.3%, respectively. OS, L-RFS, and MFS were superior in patients with marked biochemical response (CA 19-9 decrease ≥50% vs <50%; OS: 42.3 vs 24.3 months, P < 0.001; L-RFS-27.3 vs 14.1 months, P = 0.042; MFS-29.3 vs 13 months, P = 0.047) and pathological response [pCR vs pPR vs pLR: OS- not reached (NR) vs 40.3 vs 26.1 months, P < 0.001; L-RFS-NR vs 24.5 vs 21.4 months, P = 0.044; MFS-NR vs 23.7 vs 20.2 months, P = 0.017]. There was no difference in L-RFS, MFS, or OS between patients who received FLX or GNP. CONCLUSION: This large, multicenter study shows that improved biochemical, pathological, and clinical responses associated with NAC FLX or GNP result in improved OS, L-RFS, and MFS in PDAC. NAC with FLX or GNP has similar survival outcomes.
doi: https://doi.org/10.1097/SLA.0000000000003468
- A Novel Validated Recurrence Risk Score to Guide a Pragmatic Surveillance Strategy After Resection of Pancreatic Neuroendocrine Tumors: An International Study of 1006 Patients
Annals of surgery 2019 Sep;270(3):422-433
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31283562
OBJECTIVE: Despite heterogeneous biology, similar surveillance schemas are utilized after resection of all pancreatic neuroendocrine tumors (PanNETs). Given concerns regarding excess radiation exposure and financial burden, our aim was to develop a prognostic score for disease recurrence to guide individually tailored surveillance strategies. METHODS: All patients with primary nonfunctioning, nonmetastatic well/moderately differentiated PanNETs who underwent curative-intent resection at 9-institutions from 2000 to 2016 were included (n = 1006). A Recurrence Risk Score (RRS) was developed from a randomly selected derivation cohort comprised of 67% of patients and verified on the validation-cohort comprised of the remaining 33%. RESULTS: On multivariable analysis, patients within the derivation cohort (n = 681) with symptomatic tumors (jaundice, pain, bleeding), tumors >2 cm, Ki67 >3%, and lymph node (LN) (+) disease had increased recurrence. Each factor was assigned a score based on their weighted odds ratio that formed a RRS of 0 to 10: symptomatic = 1, tumor >2 cm = 2, Ki67 3% to 20% = 1, Ki67 >20% = 6, LN (+) = 1. Patients were grouped into low- (RRS = 0-2; n = 247), intermediate-(RRS = 3-5; n = 204), or high (RRS = 6-10; n = 9)-risk groups. At 24 months, 33% of high RRS recurred, whereas only 2% of low and 14% of intermediate RRS recurred. This persisted in the validation cohort (n = 325). CONCLUSIONS: This international, novel, internally validated RRS accurately stratifies recurrence-free survival for patients with resected PanNETs. Given their unique recurrence patterns, surveillance intervals of 12, 6, and 3 months are proposed for low, intermediate, and high RRS patients, respectively, to minimize radiation exposure and optimize cost/resource utilization.
doi: https://doi.org/10.1097/SLA.0000000000003461
- Well-differentiated Pancreatic Neuroendocrine Tumor in a Patient With Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM)
The American journal of surgical pathology 2019 Sep;43(9):1297-1302
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31261289
Germline mutations in CDKN2A result in Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM), which is associated with an increased risk for pancreatic ductal adenocarcinoma and melanoma. CDKN2A is somatically inactivated in multiple neoplasms, raising the possibility that, although the data are not conclusive, germline CDKN2A mutation may also impose an increased risk for other neoplasms. We present a patient with a CDKN2A germline mutation (p16-Leiden mutation) and mosaicism for neurofibromatosis type 2, who presented with a small asymptomatic pancreatic lesion, detected during endoscopic ultrasound screening of the pancreas. After resection, the lesion was found to be a well-differentiated pancreatic neuroendocrine tumor (PanNET). Molecular analysis of the tumor showed somatic loss of the second allele, supporting a causal relation of the PanNET to the underlying FAMMM syndrome. Recent data, showing the association between certain single-nucleotide polymorphisms in the CDKN2A gene and an increased incidence for PanNET, further support a role for germline CDKN2A alterations in PanNET risk. We conclude that PanNETs can be a phenotypic expression of FAMMM syndrome. This can have implications for screening and for the diagnosis of pancreatic neoplasms in carriers of germline CDKN2A mutations.
doi: https://doi.org/10.1097/PAS.0000000000001314
- miR-199a-3p targets ETNK1 to promote invasion and migration in gastric cancer cells and is associated with poor prognosis
Pathology, research and practice 2019 Sep;215(9):152511
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31255331
PURPOSE: To investigate the prognostic significance of miR-199a-3p and its role in invasion and metastasis in gastric cancer. METHODS: miR-199a-3p expression in 436 formalin-fixed and 39 frozen gastric cancer tissues was investigated by in situ hybridization and RT-PCR, respectively. The role of miR-199a-3p in the migration and invasion of gastric cancer cells was determined in overexpression and inhibitor studies using transwell assays and the SGC-7901, BGC-823 and MGC-803 gastric cancer cells lines. The effect of miR-199a-3p expression on ethanolamine kinase 1 (ETNK1) levels was determined by western botting. RESULTS: miR-199a-3p was significantly up-regulated in AGS, SGC-7901, BGC-823 and MGC-803 gastric cancer cells, when compared with GES-1 non-malignant gastric epithelial cells. In situ hybridization studies revealed that human non-tumor gastric mucosa samples were negative for miR-199a-3p expression, while 162 of 436 (37.16%) cases of gastric cancer demonstrated positive expression. miR-199a-3p overexpression was associated with tumor size, Lauren classification, depth of invasion, lymph node and distant metastasis, TNM stage and prognosis. In patients with I, II and III stage tumors, high miR-199a-3p expression was associated with a significantly lower 5-year survival rate. miR-199a-3p overexpression was associated with increased cell migration and invasion. ETNK1 expression was inhibited following miR-199a-3p overexpression in BGC-823 and SGC-7901 cells, and elevated following miR-199a-3p suppression in MGC-803 cells. CONCLUSION: miR-199a-3p is highly expressed in gastric cancer, and correlates with invasion, metastasis and prognosis. miR-199a-3p regulates the invasion and migration of gastric cancer cells by targeting ETNK1. Consequently, miR-199a-3p may serve as a prognostic indicator in gastric cancer.
doi: https://doi.org/10.1016/j.prp.2019.152511
- Cytopathology of anaplastic carcinoma of the pancreas: Review of a rare entity and description of a variant with signet ring cell features
Diagnostic cytopathology 2019 Sep;47(9):956-960
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31254330
Anaplastic carcinoma of the pancreas (ACP) is a rare and aggressive variant of pancreatic ductal adenocarcinoma (PDAC). Several studies have attempted to characterize this subtype through case series or single case reports; however, ACP remains underrecognized by cytopathologists in particular, and often lumped under the umbrella of classic PDAC. Here, we review the most up to date data that literature provides about ACP, to bring familiarity with this entity to the cytopathology practice, and to elucidate the role cytopathologists can play in recognizing and diagnosing this subtype on pancreatic aspiration biopsy, before surgical resection. We also describe a rare case of ACP, demonstrating signet ring cell features, that was diagnosed on fine needle aspiration of a pancreatic mass.
doi: https://doi.org/10.1002/dc.24263
- Of scientists and tweets
Nature reviews. Cancer 2019 Sep;19(9):479-480
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31253855
doi: https://doi.org/10.1038/s41568-019-0170-4
- Cytohistological diagnosis of pancreatic serous cystadenoma: a multimodal approach
Journal of clinical pathology 2019 Sep;72(9):615-621
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31235542
AIMS: Serous cystadenomata (SCAs) are benign pancreatic cystic neoplasms that present a diagnostic challenge despite many investigational approaches. Notwithstanding the promise of molecular diagnostics, these tests have limited accessibility in day-to-day surgical pathology practices. We aim to corroborate and build on recent evidence which suggests that positive α-inhibin immunohistochemistry (IHC) is a helpful adjunct in the biopsy confirmation of pancreatic SCA. METHODS: We retrospectively reviewed 22 fine-needle aspirates/biopsies from 14 patients (mean age 65 years, 47-83 years) with pancreatic multicystic lesions radiologically suspicious for SCA (location: 6 body, 2 head, 4 tail, 1 neck, 1 uncinate; cyst size: mean 3.7 cm, 2.0-7.6 cm), as well as an additional 10 pancreatic resection specimens with confirmed SCA; α-inhibin IHC was performed on all cell blocks, biopsy slides and representative resection specimen sections. Where available, associated cyst fluid was analysed for correlative vascular endothelial growth factor A (VEGF-A) and carcinoembryonic antigen levels. RESULTS: An α-inhibin IHC sensitivity of 80% was observed in the cases with resection confirmed SCA. Of the fine-needle aspirate/biopsy specimens, 59% (13/22) contained epithelial cells strongly positive for α-inhibin. When selecting for specimens that exhibited distinct strips of epithelium, the α-inhibin strong positivity rate increased to 73% (8/11). VEGF-A values were supportive of false-negative α-inhibin IHC in three cases and true-negative α-inhibin IHC in one case. CONCLUSION: This study postulates a diagnostic algorithm to confirm pancreatic SCA which may help to decrease unnecessary follow-up endoscopy/surgical resection and would decrease the associated morbidity, mortality and financial costs in patients with this otherwise benign condition.
doi: https://doi.org/10.1136/jclinpath-2019-205872
- Accurate and Dynamic Monitoring of Pancreatic Endocrine Function Is Required in Discharged Patients With Necrotizing Pancreatitis
Gastroenterology 2019 09;157(3):892
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31228436
doi: https://doi.org/10.1053/j.gastro.2018.12.052
- Quality of Life Following Major Laparoscopic or Open Pancreatic Resection
Annals of surgical oncology 2019 Sep;26(9):2985-2993
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31228131
PURPOSE: This study was designed to compare quality of life (QoL) among patients who underwent open versus laparoscopic pancreatic resection, including distal pancreatectomy and pancreaticoduodenectomy, and to identify clinical characteristics that are associated with changes in QoL. METHODS: Quality of life (QoL) was assessed in patients undergoing pancreatic resection with the Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire preoperatively and 2 weeks, 1, 3, and 6 months postoperatively. Multilevel regression modeling was used to determine the variability in each QoL domain within the first 2 weeks (postoperative period) and thereafter (recovery period). RESULTS: Among 159 patients, 60.4% underwent open and 39.6% underwent laparoscopic surgery. Physical, functional, hepatobiliary, and total QoL scores decreased in the postoperative period but returned to baseline levels by 6 months postoperatively. Emotional QoL improved from baseline by 2 weeks after surgery (p < 0.001) and social QoL improved from baseline by 3 months after surgery (p < 0.001). Emotional QoL was the only domain where significant differences were observed in QoL in the postoperative and recovery periods between patients who underwent open and laparoscopic pancreatic resection. Controlling for surgical approach, patients who experienced a grade III or IV complication experienced greater declines in physical, functional, hepatobiliary, and total QoL in the postoperative period. The negative impact of complications on QoL resolved by 6 months postoperatively. CONCLUSIONS: The impact of pancreatic resection on QoL was comparable between patients who underwent laparoscopic versus open pancreatic resection. Complications were strongly associated with changes in postoperative QoL, suggesting that performing a safe operation is the best approach for optimizing patient reported QoL.
doi: https://doi.org/10.1245/s10434-019-07449-x
- Outcomes of Lymph Node Dissection for Non-metastatic Pancreatic Neuroendocrine Tumors: A Propensity Score-Weighted Analysis of the National Cancer Database
Annals of surgical oncology 2019 Sep;26(9):2722-2729
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31209670
BACKGROUND: Although the National Comprehensive Cancer Network (NCCN) guidelines recommend use of lymph node dissection (LND) in patients with pancreatic neuroendocrine tumors (pNETs) > 2 cm, there is limited evidence to support the association between use of LND and overall survival (OS). METHODS: Patients with resected pNETs were identified in the National Cancer Database (2004-2014). The inverse probability of treatment weighting (IPTW) method was used to reduce the selection bias. IPTW-adjusted Kaplan-Meier curves and Cox proportional hazards models were used to compare OS of patients in different treatment groups. RESULTS: A total of 2664 patients diagnosed met the study entry criteria. Of these, 2132 patients (80.6%) received LND, with a median of nine nodes removed. Positive nodes were identified in 28.0% of patients who underwent LND. IPTW-adjusted Kaplan-Meier analysis showed that median OS was similar between the LND and LND-omitted groups (152.8 vs. 147.3 months; p = 0.61). In IPTW-adjusted Cox proportional hazards regression analysis, LND was not associated with an OS benefit (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.94-1.42; p = 0.18). The results were consistent across subgroups stratified by clinical T and N stages. Among patients with lymph node metastasis, the number of removed nodes (NRN) above the median was not associated with an improved OS (HR 0.82, 95% CI 0.60-1.13; p = 0.22). CONCLUSIONS: LND had no additional therapeutic benefit among patients undergoing resection for pNETs. The present findings should be considered when managing patients with resectable pNETs.
doi: https://doi.org/10.1245/s10434-019-07506-5
- Cross Validation of the Monoclonal Antibody Das-1 in Identification of High-Risk Mucinous Pancreatic Cystic Lesions
Gastroenterology 2019 09;157(3):720-730.e2
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31175863
BACKGROUND & AIMS: Although pancreatic cystic lesions (PCLs) are frequently and incidentally detected, it is a challenge to determine their risk of malignancy. In immunohistochemical and enzyme-linked immunosorbent assay (ELISA) analyses of tissue and cyst fluid from pancreatic intraductal papillary mucinous neoplasms, the monoclonal antibody Das-1 identifies those at risk for malignancy with high levels of specificity and sensitivity. We aimed to validate the ability of Das-1 to identify high-risk PCLs in comparison to clinical guidelines and clinical features, using samples from a multicenter cohort. METHODS: We obtained cyst fluid samples of 169 PCLs (90 intraductal papillary mucinous neoplasms, 43 mucinous cystic neoplasms, and 36 non-mucinous cysts) from patients undergoing surgery at 4 tertiary referral centers (January 2010 through June 2017). Histology findings from surgical samples, analyzed independently and centrally re-reviewed in a blinded manner, were used as the reference standard. High-risk PCLs were those with invasive carcinomas, high-grade dysplasia, or intestinal-type intraductal papillary mucinous neoplasms with intermediate-grade dysplasia. An ELISA with Das-1 was performed in parallel using banked cyst fluid samples. We evaluated the biomarker’s performance, generated area under the curve values, and conducted multivariate logistic regression using clinical and pathology features. RESULTS: The ELISA for Das-1 identified high-risk PCLs with 88% sensitivity, 99% specificity, and 95% accuracy, at a cutoff optical density value of 0.104. In 10-fold cross-validation analysis with 100 replications, Das-1 identified high-risk PCLs with 88% sensitivity and 98% specificity. The Sendai, Fukuoka, and American Gastroenterological Association guideline criteria identified high-risk PCLs with 46%, 52%, and 74% accuracy (P for comparison to Das-1 ELISA <.001). When we controlled for Das-1 in multivariate regression, main pancreatic duct dilation >5 mm (odds ratio, 14.98; 95% confidence interval, 2.63-108; P < .0012), main pancreatic duct dilation ≥1 cm (odds ratio, 47.9; 95% confidence interval, 6.39-490; P < .0001), and jaundice (odds ratio, 6.16; 95% confidence interval, 1.08-36.7; P = .0397) were significantly associated with high-risk PCLs. CONCLUSIONS: We validated the ability of an ELISA with the monoclonal antibody Das-1 to detect PCLs at risk for malignancy with high levels of sensitivity and specificity. This biomarker might be used in conjunction with clinical guidelines to identify patients at risk for malignancy.
doi: https://doi.org/10.1053/j.gastro.2019.05.014
- The Pathologic and Genetic Characteristics of the Intestinal Subtype of Intraductal Papillary Neoplasms of the Bile Duct
The American journal of surgical pathology 2019 Sep;43(9):1212-1220
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31166202
The present study aimed to identify the pathologic and genetic characteristics of intestinal subtype of intraductal papillary neoplasm of the bile duct (iIPNB) showing columnar cells with pseudostratified, cigar-shaped nuclei, and basophilic or amphophilic cytoplasm with the diffuse immunohistochemical expression of CK20 and/or CDX2. A total of 34 cases of iIPNB were pathologically examined according to their anatomic location (the bile duct) and were then compared with the intestinal subtype of intraductal papillary mucinous neoplasm (iIPMN) of the pancreas (n=22). Mutations of 26 somatic genes were examined in formalin-fixed paraffin-embedded tissue specimens from 21 cases of iIPNB using the TruSight Tumor 26 gene panel and next-generation sequencing. iIPNB cases were divided into intrahepatic (n=6) and extrahepatic (n=28) categories. Intrahepatic IPNBs showed a less-complicated villous-papillary pattern, while extrahepatic IPNBs showed a papillary pattern with tubular and/or villous components and predominant high-grade dysplasia with complicated architectures. MUC5AC was frequently and extensively expressed in intrahepatic iIPNBs and iIPMNs but not in extrahepatic iIPNBs. CD10 was frequently expressed in extrahepatic IPNBs but not in intrahepatic iIPNBs or iIPMN. Genetic mutations of TP53 and PIK3CA, which were infrequent or absent in iIPMNs, were frequently detected in extrahepatic iIPNBs, while KRAS and GNAS, which were commonly observed in iIPMNs, were frequently detected in intrahepatic iIPNBs. Intrahepatic iIPNBs showed villous-papillary growth with features reminiscent of iIPMNs, while extrahepatic iIPNBs showed papillary growth with tubular and/or villous components, complicated histology and variable differences from iIPMNs, suggesting differences in the tumorigenesis of iIPNBs along the biliary tree.
doi: https://doi.org/10.1097/PAS.0000000000001295
- Axon Guidance Molecules Promote Perineural Invasion and Metastasis of Orthotopic Pancreatic Tumors in Mice
Gastroenterology 2019 09;157(3):838-850.e6
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31163177
BACKGROUND & AIMS: Little is known about mechanisms of perineural invasion (PNI) by pancreatic ductal adenocarcinomas (PDAs) or other tumors. Annexin A2 (ANXA2) regulates secretion of SEMA3D, an axon guidance molecule, which binds and activates the receptor PLXND1 to promote PDA invasion and metastasis. We investigated whether axon guidance molecules promote PNI and metastasis by PDA cells in mice. METHODS: We performed studies in a dorsal root ganglion (DRG) invasion system, wild-type C57BL/6 mice (controls), mice with peripheral sensory neuron-specific disruption of PlxnD1 (PLAC mice), LSL-KRASG12D/+;LSL-TP53R172H/+;PDX-1-CRE+/+ (KPC) mice, and KPC mice crossed with ANXA2-knockout mice (KPCA mice). PDA cells were isolated from KPC mice and DRG cells were isolated from control mice. Levels of SEMA3D or ANXA2 were knocked down in PDA cells with small hairpin and interfering RNAs and cells were analyzed by immunoblots in migration assays, with DRGs and with or without antibodies against PLXND1. PDA cells were injected into the pancreas of control and PLAC mice, growth of tumors was assessed, and tumor samples were analyzed by histology. DRG cells were incubated with SEMA3D and analyzed by live imaging. We measured levels of SEMA3D and PLXND1 in PDA specimens from patients with PNI and calculated distances between tumor cells and nerves. RESULTS: DRG cells increase the migration of PDC cells in invasion assays; knockdown of SEMA3D in PDA cells or antibody blockade of PLXND1 on DRG cells reduced this invasive activity. In mice, orthotopic tumors grown from PDA cells with knockdown of SEMA3D, and in PLAC mice, orthotopic tumors grown from PDA cells, had reduced innervation and formed fewer metastases than orthotopic tumors grown from PDA cells in control mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. CONCLUSIONS: DRG cells increase the migratory and invasive activities of pancreatic cancer cells, via secretion of SEMA3D by pancreatic cells and activation of PLXND1 on DRGs. Knockdown of SEMA3D and loss of neural PLXND1 reduces innervation of orthotopic PDAs and metastasis in mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. Strategies to disrupt the axon guidance pathway mediated by SEMA3D and PLXND1 might be developed to slow progression of PDA.
doi: https://doi.org/10.1053/j.gastro.2019.05.065
- Cholangiographic Tumor Classification for Simple Patient Selection Prior to Hepatopancreatoduodenectomy for Cholangiocarcinoma
Annals of surgical oncology 2019 Sep;26(9):2971-2979
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31102092
BACKGROUND: Hepatopancreatoduodenectomy (HPD) is employed for patients with laterally advanced cholangiocarcinoma. However, the survival benefit of this extended approach remains controversial. The aim of this study is to identify a tumor feature benefiting from HPD from the standpoint of long-term survival. PATIENTS AND METHODS: Patients with cholangiocarcinoma who underwent HPD with curative intent between 2001 and 2017 were retrospectively analyzed. Tumors were radiologically classified by preoperative cholangiogram. Diffuse type was defined as significant tumor/stricture located from the hilar to intrapancreatic duct; localized type was defined as tumor otherwise. Univariable and multivariable analyses were performed to identify prognostic indicators. RESULTS: Of 100 study patients, 28 (28%) patients had diffuse tumor type, while the remaining 72 (72%) patients had localized tumors. The former group showed significantly longer lateral length (43 versus 22 mm, P < 0.001) and more frequent pancreatic invasion (50% versus 32%, P = 0.110), advanced T classification (64% versus 49%, P = 0.185), and nodal metastasis (57% versus 47%, P = 0.504), compared with the latter group. The survival for patients with diffuse tumor type was significantly worse than that for patients with localized tumor type, with 5-year survival rates of 59.0% versus 26.3%, respectively (P = 0.003). Multivariable analysis identified four independent factors deteriorating long-term survival: cholangiographic diffuse tumor (P = 0.021), higher age (P = 0.020), percutaneous biliary drainage (P = 0.007), and portal vein resection (P = 0.007). CONCLUSIONS: Presurgical cholangiographic classification, diffuse or localized type, is a tumor-related factor closely associated with survival probability; therefore, it may be a useful feature for patient selection prior to HPD for cholangiocarcinoma.
doi: https://doi.org/10.1245/s10434-019-07457-x
- Understanding the mechanisms of reversal of type 2 diabetes
The lancet. Diabetes & endocrinology 2019 Sep;7(9):726-736
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31097391
Clinical and pathophysiological studies have shown type 2 diabetes to be a condition mainly caused by excess, yet reversible, fat accumulation in the liver and pancreas. Within the liver, excess fat worsens hepatic responsiveness to insulin, leading to increased glucose production. Within the pancreas, the β cell seems to enter a survival mode and fails to function because of the fat-induced metabolic stress. Removal of excess fat from these organs via substantial weight loss can normalise hepatic insulin responsiveness and, in the early years post-diagnosis, is associated with β-cell recovery of acute insulin secretion in many individuals, possibly by redifferentiation. Collectively, these changes can normalise blood glucose levels. Importantly, the primary care-based Diabetes Remission Clinical Trial (DiRECT) showed that 46% of people with type 2 diabetes could achieve remission at 12 months, and 36% at 24 months, mediated by weight loss. This major change in our understanding of the underlying mechanisms of disease permits a reassessment of advice for people with type 2 diabetes.
doi: https://doi.org/10.1016/S2213-8587(19)30076-2
- Rapid research autopsy is a stealthy but growing contributor to cancer research
Cancer 2019 Sep;125(17):2915-2919
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31090935
doi: https://doi.org/10.1002/cncr.32184
- Biomarkers to diagnose metastatic breast carcinoma to the pancreas: A case report and update
Diagnostic cytopathology 2019 Sep;47(9):912-917
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31087784
The patient is a 72-year-old female who presents with new onset jaundice. The patient has a past medical history significant for right-sided estrogen receptor (ER)-positive and left-sided ER-negative breast cancers in 2005 and 2009, respectively, and recent 1-year history of ER-positive right-sided breast cancer with bone and brain metastases. CT scan and endoscopic ultrasound (EUS) revealed a new 2 cm mass in the head of the pancreas, leading to EUS-guided fine-needle aspiration of the lesion. Pathologic workup revealed adenocarcinoma with signet-ring cells, representing either metastatic breast or primary pancreatic cancer. Immunohistochemistry and molecular diagnostic workup identified positive GATA-binding protein 3 (GATA3) immunoreactivity and a mutation in Erb-B2 receptor tyrosine kinase 2 (ERBB2), also known as human epidermal growth factor receptor 2 (HER2). Here, we review the diagnostic markers commonly used to differentiate metastatic breast vs primary pancreatic adenocarcinoma, and discuss the challenges of utilizing GATA3 immunoreactivity and ERBB2 mutations for diagnosis.
doi: https://doi.org/10.1002/dc.24210
- Pancreatic panniculitis in active systemic lupus erythematosus
Journal of cutaneous pathology 2019 Sep;46(9):688-690
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31081550
This report documents the case of a 64-year-old African-American female with new end-stage renal disease (ESRD), diagnosed with systemic lupus erythematosus (SLE) on renal biopsy and serologies including a positive ANA (>1:2560), positive anti-Sm antibodies, low titer anti-RNP antibodies, high titer anti-Ro antibodies, anti-dsDNA antibodies, lupus anticoagulant, and hypocomplementemia. She was also noted to have tender nodules on the bilateral shins. Excisional biopsy of one of the nodules showed marked fat necrosis with “ghost cells” and patchy basophilic granular debris consistent with pancreatic panniculitis. Further examination for pancreatic pathology showed an elevated lipase of 585 U/L (reference range 8-78 U/L) and amylase of 214 U/L (reference range 25-125 U/L). However, computed tomography imaging showed no evidence of pancreatitis or pancreatic tumors. This is very similar to another case recently reported in the literature. Similarities of these two cases (African-American females with lupus nephritis on dialysis) may represent a particular subset of SLE patients at increased risk for pancreatic panniculitis.
doi: https://doi.org/10.1111/cup.13493
- Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia
Gastroenterology 2019 09;157(3):823-837
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31078621
BACKGROUND & AIMS: Most pancreatic ductal adenocarcinomas (PDACs) express an activated form of KRAS, become hypoxic and dysplastic, and are refractory to chemo and radiation therapies. To survive in the hypoxic environment, PDAC cells upregulate enzymes and transporters involved in pH regulation, including the extracellular facing carbonic anhydrase 9 (CA9). We evaluated the effect of blocking CA9, in combination with administration of gemcitabine, in mouse models of pancreatic cancer. METHODS: We knocked down expression of KRAS in human (PK-8 and PK-1) PDAC cells with small hairpin RNAs. Human and mouse (KrasG12D/Pdx1-Cre/Tp53/RosaYFP) PDAC cells were incubated with inhibitors of MEK (trametinib) or extracellular signal-regulated kinase (ERK), and some cells were cultured under hypoxic conditions. We measured levels and stability of the hypoxia-inducible factor 1 subunit alpha (HIF1A), endothelial PAS domain 1 protein (EPAS1, also called HIF2A), CA9, solute carrier family 16 member 4 (SLC16A4, also called MCT4), and SLC2A1 (also called GLUT1) by immunoblot analyses. We analyzed intracellular pH (pHi) and extracellular metabolic flux. We knocked down expression of CA9 in PDAC cells, or inhibited CA9 with SLC-0111, incubated them with gemcitabine, and assessed pHi, metabolic flux, and cytotoxicity under normoxic and hypoxic conditions. Cells were also injected into either immune-compromised or immune-competent mice and growth of xenograft tumors was assessed. Tumor fragments derived from patients with PDAC were surgically ligated to the pancreas of mice and the growth of tumors was assessed. We performed tissue microarray analyses of 205 human PDAC samples to measure levels of CA9 and associated expression of genes that regulate hypoxia with outcomes of patients using the Cancer Genome Atlas database. RESULTS: Under hypoxic conditions, PDAC cells had increased levels of HIF1A and HIF2A, upregulated expression of CA9, and activated glycolysis. Knockdown of KRAS in PDAC cells, or incubation with trametinib, reduced the posttranscriptional stabilization of HIF1A and HIF2A, upregulation of CA9, pHi, and glycolysis in response to hypoxia. CA9 was expressed by 66% of PDAC samples analyzed; high expression of genes associated with metabolic adaptation to hypoxia, including CA9, correlated with significantly reduced survival times of patients. Knockdown or pharmacologic inhibition of CA9 in PDAC cells significantly reduced pHi in cells under hypoxic conditions, decreased gemcitabine-induced glycolysis, and increased their sensitivity to gemcitabine. PDAC cells with knockdown of CA9 formed smaller xenograft tumors in mice, and injection of gemcitabine inhibited tumor growth and significantly increased survival times of mice. In mice with xenograft tumors grown from human PDAC cells, oral administration of SLC-0111 and injection of gemcitabine increased intratumor acidosis and increased cell death. These tumors, and tumors grown from PDAC patient-derived tumor fragments, grew more slowly than xenograft tumors in mice given control agents, resulting in longer survival times. In KrasG12D/Pdx1-Cre/Tp53/RosaYFP genetically modified mice, oral administration of SLC-0111 and injection of gemcitabine reduced numbers of B cells in tumors. CONCLUSIONS: In response to hypoxia, PDAC cells that express activated KRAS increase expression of CA9, via stabilization of HIF1A and HIF2A, to regulate pH and glycolysis. Disruption of this pathway slows growth of PDAC xenograft tumors in mice and might be developed for treatment of pancreatic cancer.
doi: https://doi.org/10.1053/j.gastro.2019.05.004
- In Patients with Localized and Resectable Gastric Cancer, What is the Optimal Extent of Lymph Node Dissection-D1 Versus D2 Versus D3?
Annals of surgical oncology 2019 Sep;26(9):2912-2932
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31076930
BACKGROUND: Despite advances in the treatment of patients with gastric cancer, the debate over the optimal extent of lymphadenectomy continues. METHOD: A review of the classification, rationale for, and boundaries of lymphadenectomy is presented. A review of the available literature comparing D1 versus D2 versus D3 lymphadenectomy was performed and included randomized controlled trials, and prospective and retrospective comparative and non-comparative studies. RESULTS: Earlier studies demonstrated increased morbidity with D2 compared with D1 lymphadenectomy, with no significant survival benefit. More recent studies have demonstrated survival benefit of a pancreas and spleen-sparing D2 lymphadenectomy in patients with advanced, node-positive tumors. Para-aortic/D3 dissections contribute to increased morbidity, with no survival benefit. CONCLUSIONS: In patients with resectable gastric adenocarcinoma, a D2 lymph node dissection preserving the pancreas and spleen should be considered standard for optimal staging and treatment, provided it is performed by surgeons with sufficient expertise. Extended lymph node dissections beyond D2 should not be routinely performed as it has been shown to have increased morbidity, with no improvement in outcomes. While systemic chemotherapy should be considered standard in patients undergoing D2 lymphadenectomy, the role of adjuvant radiation continues to evolve.
doi: https://doi.org/10.1245/s10434-019-07417-5
- The role of rapid on-site evaluation on diagnostic accuracy of endoscopic ultrasound fine needle aspiration for pancreatic, submucosal upper gastrointestinal tract and adjacent lesions
Cytopathology : official journal of the British Society for Clinical Cytology 2019 Sep;30(5):499-503
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31034112
BACKGROUND AND AIM: Our aim was to assess adequacy and diagnostic accuracy of endoscopic ultrasound-fine needle aspiration (EUS-FNA) specimens with or without rapid on-site evaluation (ROSE) from pancreatic, upper gastrointestinal tract (UGIT) and adjacent masses. METHOD: A retrospective cohort study based on patients’ files who underwent EUS-FNA in Galilee Medical Center in a 4 years period. Number of needle passes, repeated EUS and ROSE effect on tissue adequacy and diagnostic accuracy were reported. RESULTS: One-hundred sixty-one patients were included. Ninety-three patients (57.7%) underwent EUS-FNA without ROSE (group A) compared to 68 patients (42.3%) with ROSE (group B). The most common location was in the pancreas (55% in group A vs 81% in group B). Addition of ROSE yielded a significantly higher specimen adequacy (65% in group A vs 92.6% in group B (Chi-Square < 0.0001, OR 6.72, 95% CI 2.45-18.38). The matching rate (accuracy) between ROSE diagnosis and final histopathological diagnosis was noticed in 61 out of 68 patients (89.7%, 95% CI 0.7993-0.9576). The Kappa coefficient correlations of matching rate between ROSE and final histopathological diagnosis of all lesion and in pancreatic lesions were 0.7558, (95% CI 0.625-0.887) and 0.7814, (95% CI 0.639-0.924), respectively. CONCLUSIONS: EUS-FNA with ROSE significantly improve specimen adequacy and was associated with high diagnostic accuracy.
doi: https://doi.org/10.1111/cyt.12712
- Acute Methamphetamine-Induced Hepatic and Pancreatic Ischemia
The American journal of forensic medicine and pathology 2019 Sep;40(3):285-288
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31033491
Methamphetamine is a central nervous system stimulant that induces arousal, a positive mood, cardiac stimulation, and an acute improvement in cognitive domains. Its illicit exploitation is rapidly growing in North America. Typically, extended use of the drug induces organ damage via vasoconstriction and subsequent ischemia. This case specifically discusses hepatic and pancreatic pathology resulting from methamphetamine overdose alongside an unusual discovery of globally necrotic von Meyenburg complexes.
doi: https://doi.org/10.1097/PAF.0000000000000486
- Keratin 19-expressing hepatocellular carcinoma and small-duct type intrahepatic cholangiocarcinoma show a similar postoperative clinical course but have distinct genetic features
Histopathology 2019 Sep;75(3):385-393
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31017316
AIMS: The present study aimed to systematically compare clinicopathological and genetic features between keratin 19 (K19)-expressing hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). METHODS AND RESULTS: Consecutive cases of HCC (n = 430) were classified into K19+ and K19- using immunohistochemistry. ICCA cases were also separated into small-(S-iCCA; n = 36) and large-duct types (n = 22) based on recently proposed criteria, with the former being used in the present study. Mutational hot-spots in TERT, CTNNB1, KRAS and IDH1 were sequenced. Twenty-six cases (6%) of HCC expressed K19. K19+ HCC was more strongly associated with chronic hepatitis B than K19- HCC and S-iCCA (46% versus 17% and 6%; both P < 0.001). Lymph node metastasis was observed in K19+ HCC (8%) and S-iCCA (22%), but was exceptional in K19- HCC (1%). K19+ HCC had TERT promoter mutations less frequently than K19- HCC (31% versus 59%; P = 0.022), and lacked alterations in KRAS and IDH1. CTNNB1 mutations were similarly observed in K19+ and K19- HCC (23% and 19%, respectively), but rare in S-iCCA (3%). The postoperative survival curve of K19+ HCC was almost identical to that of S-iCCA in the first 5 years (approximately 50% at 5 years), and significantly worse than that of K19- HCC (P = 0.040). Extrahepatic recurrence was more common in K19+ HCC (50%) and S-iCCA (35%) than in K19- HCC (15%) (P = 0.001). CONCLUSIONS: Although K19+ HCC and S-iCCA showed similar biological behaviours, they did not share any driver gene mutations, suggesting the possible involvement of epigenetic alterations in the iCCA-like features of K19+ HCC.
doi: https://doi.org/10.1111/his.13884
- Addition of analysis of KRAS mutation or immunohistochemistry with MUC1 and carcinoembryonic antigen improves the diagnostic performance of fine needle aspiration cytology for the diagnosis of pancreatic carcinoma
Cytopathology : official journal of the British Society for Clinical Cytology 2019 Sep;30(5):485-491
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30929285
BACKGROUND: Pancreatic adenocarcinoma (PAC) is a health problem because of high lethality, increasing incidence and the absence of an early diagnosis. Biopsy by fine needle aspiration guided by endoscopic ultrasound has allowed obtaining tissue for cytopathological analysis, but there are several problems with their interpretation. We aimed to compare the diagnostic performance of the cytopathological analysis with the addition of either an immunohistochemical (IHC) panel or the KRAS mutation for the diagnosis of PAC. METHODS: We evaluated 62 pancreatic lesions by fine needle aspiration guided by endoscopic ultrasound, applying an IHC panel with mucin (MUC)-1, MUC4, carcinoembryonic antigen (CEA) and p53. All cases also had a KRAS mutation determination. Three cytopathologists blinded to clinical data and the KRAS status reviewed the cytology independently. We calculated diagnostic performances for the cytology alone, cytology+IHC and cytology+KRAS to show the best method to diagnose PAC. RESULTS: From 62 samples, 50 (80.6%) were PAC and 12 benign lesions. The cytopathological analysis correctly interpreted 26 malignant and 12 non-neoplastic cases (sensitivity 52%, specificity 100% and diagnostic accuracy 61.3%). The KRAS mutation was present in 88% of PAC. The cytology+ KRAS mutation increased the sensitivity by 10% and the diagnostic accuracy by 8%. The sensitivity increased by 2% adding either MUC1 or CEA to the cytology, and the diagnostic accuracy by 10 or 18%, respectively. CONCLUSION: The addition of IHC either with CEA or MUC1 improved the diagnostic performance of the cytology alone to diagnose PAC. The cytology + IHC evaluation was superior to the cytology + KRAS mutation to diagnose PAC.
doi: https://doi.org/10.1111/cyt.12697
- IL-33 overexpression in gallbladder cancers associated with pancreatobiliary maljunction
Histopathology 2019 Sep;75(3):365-375
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30882917
AIMS: To investigate whether genetic or inflammatory pro-oncogenic factors are relevant to the increased risk of gallbladder cancers in patients with pancreaticobiliary maljunction (PBM). METHODS AND RESULTS: Mutations in KRAS exon 2 were examined by a highly sensitive, droplet digital PCR platform using surgically resected specimens of PBM-associated (n = 31) and non-associated gallbladder cancers (n = 49). The tissue expression of IL-6 and IL-33, which are suspected to promote biliary carcinogenesis, was analysed by quantitative real-time PCR and in-situ hybridisation. The incidence of KRAS mutations was similarly low in PBM-associated (five of 32 cases; 16%) and non-associated cancers (four of 49 cases; 8%) (P = 0.272). The tissue expression of IL-33 mRNA, but not IL-6 mRNA, was significantly higher in PBM-associated gallbladder cancers than in gallbladder cancers without PBM (P = 0.004). A similar degree of IL-33 overexpression was also observed in the background non-cancerous mucosa in cases of PBM-associated gallbladder cancers, and was significantly greater than that in PBM cases with cholecystitis alone (P < 0.001). The results of in-situ hybridisation indicated that the source of IL-33 production in PBM-associated carcinomas was the endothelium, cancer cells and non-neoplastic biliary epithelium. In a combined PBM-associated and non-associated cohort, IL-33 overexpression in gallbladder cancers correlated with less aggressive features (e.g. a lower pT stage and longer overall survival), similar to recently reported findings on large-duct cholangiocarcinomas. CONCLUSIONS: KRAS mutations do not appear to be associated with a high risk of malignancy in PBM, while IL-33 overexpression may provide a pro-oncogenic microenvironment in the gallbladder mucosa of patients with PBM.
doi: https://doi.org/10.1111/his.13863
- Neuroendocrine Neoplasms Associated with Germline Pathogenic Variants in the Homologous Recombination Pathway
Endocrine pathology 2019 Sep;30(3):237-245
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30772928
Neuroendocrine neoplasms (NENs) have been primarily associated with germline pathogenic variants in genes involved in chromatin remodeling (MEN1), cell cycle control (CDKN1B), PI3K/mTOR signaling (TSC1/2, PTEN) as well as pseudohypoxia (VHL, SDHx). Recent work has implicated various genes involved in DNA repair pathways in the pathophysiology of a subset of pancreatic neuroendocrine neoplasms, including BRCA2, via the homologous recombination pathway (HRD). To date, germline variants in other HRD pathway genes have not been described to contribute to NEN. PALB2, RAD51C, and BARD1 are additional tumor suppressor genes which also mediate repair of double stranded DNA breaks through the HRD pathway and are implicated in hereditary breast (PALB2; BARD1) and ovarian (RAD51C) cancer. Here we report three cases of NEN associated with germline pathogenic variants in PALB2 (pancreatic NEN), RAD51C (thymic NEN), and BARD1 (pancreaticoduodenal NEN) respectively, further linking the DNA repair pathway to NENs.
doi: https://doi.org/10.1007/s12022-019-9569-4
- What Is the Peri-Pancreas Cystic Lesion?
Gastroenterology 2019 09;157(3):622-623
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30615877
doi: https://doi.org/10.1053/j.gastro.2018.12.029
- Acute Pancreatitis Caused by Isolated Pancreatic Metastasis From Uterine Choriocarcinoma
International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 2019 Sep;38(5):430-434
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30028356
Choriocarcinoma is an aggressive gestational trophoblastic neoplasia known for its widely metastatic potential. However, isolated pancreatic metastasis is an extremely rare occurrence and has not been documented in the English literature to the best of our knowledge. The metastatic deposits in the index case led to widespread hemorrhage and necrosis of the pancreatic parenchyma, causing severe acute pancreatitis. The patient succumbed to her illness before chemotherapy was administered. Thus, we present an autopsy case of a uterine choriocarcinoma with isolated pancreatic metastasis presenting as severe acute pancreatitis in a 27-yr-old woman following a molar pregnancy.
doi: https://doi.org/10.1097/PGP.0000000000000532
- Systematic Selective Sampling of Cholecystectomy Specimens is Adequate to Detect Incidental Gallbladder Adenocarcinoma
The American journal of surgical pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31464710
Many gallbladder adenocarcinomas (ACs) are detected incidentally in routine cholecystectomy specimens, yet sampling practices vary when intestinal metaplasia (IM) or dysplasia are found via routine sampling. Our practice has been to submit 5 additional sections when IM is found, but cases with dysplasia are entirely submitted. We sought to determine an appropriate sampling protocol when encountering these findings. We retrospectively identified cholecystectomy specimens with these features over a 26-month period, yielding 48 of 4059 (1%) cases. Four pathologists independently classified the (2 longitudinal and 1 cystic duct margin) original sections into 1 of 3 categories (IM, low-grade dysplasia [LGD] or high-grade dysplasia [HGD]); initial findings were correlated with final diagnoses. Sixteen (33%) cases had additional findings upon further sampling, including LGD (n=10) or HGD (n=4) and AC (n=2). HGD always accompanied malignancy. We prospectively analyzed 39 of 3133 (1%) additional cholecystectomy specimens, initially submitting the same routine sections. We submitted 5 random sections from cases with IM. Cases with LGD were first examined with 1 additional section per centimeter. All remaining tissue was submitted in all of these cases and separately reviewed. Cases with HGD were entirely submitted as both test cases with HGD in initial sections ultimately showed carcinoma. This protocol detected all cases of HGD and AC. Patients with clear cystic duct margins did not experience neoplastic progression, even if dysplasia was present elsewhere. We conclude gallbladders with HGD should be entirely submitted, LGD may be representatively sampled, and routine sampling is adequate for IM.
doi: https://doi.org/10.1097/PAS.0000000000001351
- Second-line chemotherapy in advanced biliary cancers: A retrospective, multicenter analysis of outcomes
Cancer 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31454426
BACKGROUND: Although gemcitabine plus platinum chemotherapy is the established first-line regimen for advanced biliary cancer (ABC), there is no standard second-line therapy. This study evaluated current practice and outcomes for second-line chemotherapy in patients with ABC across 3 US academic medical centers. METHODS: Institutional registries were reviewed to identify patients who had received second-line chemotherapy for ABC from April 2010 to March 2015 along with their demographics, diagnoses and staging, treatment histories, and clinical outcomes. Overall survival from the initiation of second-line chemotherapy (OS2) was estimated with Kaplan-Meier methods. RESULTS: This study identified 198 patients with cholangiocarcinoma (intrahepatic [61.1%] or extrahepatic [14.1%]) or gallbladder carcinoma (24.8%); 52% received at least 3 lines of systemic chemotherapy. The median OS2 was 11 months (95% confidence interval [CI], 8.8-13.1 months). The median OS2 for patients with intrahepatic cholangiocarcinoma was 13.4 months (95% CI, 10.7-17.8 months), which was longer than that for patients with extrahepatic cholangiocarcinoma (6.8 months; 95% CI, 5-10.6 months) or gallbladder carcinoma (9.4 months; 95% CI, 7.2-12.3 months; P = .018). The median time to second-line treatment failure was 2.2 months (95% CI, 1.8-2.7 months), and it was similar across tumor locations (P = .60). CONCLUSIONS: In this large cohort of patients with ABC treated across 3 academic medical centers after the failure of first-line chemotherapy, the time to treatment failure on standard therapies was short, although the median OS2 was longer than has been reported previously, and more than half of the patients received additional lines of treatment. This multicenter collaboration represents the largest cohort studied to date of second-line chemotherapy for ABC and provides a contemporary benchmark for future clinical trials.
doi: https://doi.org/10.1002/cncr.32463
- Emphysematous Cholecystitis
The New England journal of medicine 2019 Aug;381(8):e14
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31433924
doi: https://doi.org/10.1056/NEJMicm1814551
- An Uncommon Case of Double-Hit Mantle Cell Lymphoma That Demonstrates a Transformation Process
American journal of clinical pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31433838
OBJECTIVES: Mantle cell lymphoma (MCL) is a mature B-cell lymphoma characterized by CCND1/IGH rearrangement. We reported a case of MCL harboring both CCND1/IGH and MYC/IGH rearrangements that also presented with an aggressive clinical course. METHODS: Biopsy specimens were evaluated by morphological staining, immunohistochemistry, flow cytometry, conventional cytogenetics, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS). RESULTS: Morphological and immunohistochemical staining of gallbladder samples demonstrated blastoid variant MCL. However, in the bone marrow sample, FISH indicated rearrangements in CCND1/IGH and MYC/IGH. Flow cytometry identified two groups of malignant lymphocytes. We sorted these two groups of cells. NGS then revealed that both cell types carried CCND1/IGH rearrangements and TP53 mutations. Furthermore, the CD19+/CD10+ cells carried additional MYC/IGH rearrangement and NOTCH2 mutation. CONCLUSIONS: The rearrangement of MYC and a mutation in NOTCH2 probably induced the transformation of MCL cells in this patient. This uncommon double-hit MCL case clearly demonstrates a transformation process.
doi: https://doi.org/10.1093/ajcp/aqz133
- Expression of fatty-acid-binding protein 5 in intrahepatic and extrahepatic cholangiocarcinoma: the possibility of different energy metabolisms in anatomical location
Medical molecular morphology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31432248
The biliary tract cancer (BTC) covers a range of carcinomas, including intrahepatic cholangiocarcinoma (ICC), cholangiolocellular carcinoma (CoCC), perihilar cholangiocarcinoma (perihilar CC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC), defined according to the anatomical location. These adenocarcinomas mostly comprise biliary epithelial cell-derived malignant cells. In addition to anatomical differences, there are morphological and biological differences in BTC starting from embryonic development of the tissues extending to physiological differences. Fatty acid-binding proteins (FABPs) are closely associated with the energy metabolism. Using surgical specimens from 74 BTCs, we performed immunohistochemistry for FABP5 and its associated molecules, including peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator 1 (PGC-1), and estrogen-related receptor α (ERRα). We found that the expression patterns of small BTCs (ICC and CoCC) considerably differed from those of large BTCs (perihilar CC, ECC, and GBC). Expression of FABP5 and PGC-1 in large BTCs was high compared with those of small BTCs, but no difference in the expression of PPARγ and ERRα was observed. FABP5 appears to play a role in malignant progression in large BTCs. Small and large BTCs possess different energy metabolism systems owing to their different anatomical locations and course of carcinogenesis, although all BTCs originate from biliary epithelial cells.
doi: https://doi.org/10.1007/s00795-019-00230-9
- Transpapillary Endoscopic Removal of Gallbladder Stones Through a Fully Covered Metallic Stent
The American journal of gastroenterology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31403962
doi: https://doi.org/10.14309/ajg.0000000000000367
- A 12-year trend analysis of the incidence of gastrointestinal cancers in East Azerbaijan: last updated results of an ongoing population-based cancer registry
BMC cancer 2019 Aug;19(1):782
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31391032
BACKGROUND: The most recent results of Global Cancer Statistics indicated that gastrointestinal cancers, including gastric, colorectal, esophageal, and liver cancers, are among the most commonly diagnosed cancers worldwide. Previous reports from cancer registries in East Azerbaijan have shown that there is a high incidence of gastrointestinal cancer in this region, so we performed a trend analysis to determine the pattern of change over the last decade. METHODS: In total, 12 years of cancer registry data were collected from different sources in East Azerbaijan, and a data quality check was performed to ensure clean data. Using the 2000 World Health Organization standard population, we then generated age-standardized incidence rates (ASRs) for different cancers, and for each year from 1383 to 1394 of the Persian calendar (i.e., 19 March 2004 to 20 March 2015). Annual percent changes (APCs) and Average annual percent changes (AAPCs) in the ASRs for esophageal, gastric, small intestine, colorectal, anal, liver, gallbladder, and pancreatic cancers were calculated using Joinpoint Software (Version 4.5.0.1, June 2017). RESULTS: An increase in most types of cancer was observed during the study period. The ASR for colorectal cancer increased from 2.9 to 13.6 per 100,000 women (APC, 9.7%) and from 2.2 to 17.8 per 100,000 men (APC, 10.2%). The ASR for gastric cancer showed a slight increasing trend from 10.5 to 13.5 per 100,000 women (APC, 1.3%) and from 3.1 to 29.9 per 100,000 men (APC, 3.2%). However, trend analysis showed a decreasing pattern for the ASR of esophageal cancer in both genders (APC,- 3%), with APCs of - 1.1% in females and - 0.4% in males. CONCLUSIONS: The latest results of the East Azerbaijan Population-Based Cancer Registry indicate that gastrointestinal cancers remain common, with significant increasing trends in their ASRs. Improved screening and early detection are needed in this region.
doi: https://doi.org/10.1186/s12885-019-6008-3
- Classification of the cystic duct patterns and endoscopic transpapillary cannulation of the gallbladder to prevent post-ERCP cholecystitis
BMC gastroenterology 2019 Aug;19(1):139
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31382888
BACKGROUND: Endoscopic transpapillary cannulation of the gallbladder is useful but challenging. This study aimed to investigate cystic duct anatomy patterns, which may guide cystic duct cannulation. METHODS: A total of 226 patients who underwent endoscopic transpapillary cannulation of the gallbladder were analyzed retrospectively. RESULTS: According to the cystic duct take-off, 226 cystic duct patterns were divided into 3 patterns: Type I (193, 85.4%), located on the right and angled up; Type II (7, 3.1%), located on the right and angled down; and Type III (26, 11.5%), located on the left and angled up. Type I was further divided into three subtypes: Line type, S type (S1, not surrounding the common bile duct; S2, surrounding the common bile duct), and α type (α1, forward α; α2, reverse α). Types I and III cystic ducts were easier to be cannulated with a higher success rate (85.1 and 86.4%, respectively) compared with Type II cystic duct (75%) despite no statistically significant difference. The reasons for the failure of gallbladder cannulation included invisible cyst duct take-off, severe cyst duct stenosis, impacted stones in cyst duct or neck of the gallbladder, sharply angled cyst duct, and markedly dilated cyst duct with the tortuous valves of Heister. CONCLUSION: Classification of cystic duct patterns was helpful in guiding endoscopic transpapillary gallbladder cannulation.
doi: https://doi.org/10.1186/s12876-019-1053-6
- Acute Recurrent and Chronic Pancreatitis as Initial Manifestations of Cystic Fibrosis and Cystic Fibrosis Transmembrane Conductance Regulator-Related Disorders
Pancreas 2019 Aug;48(7):888-893
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31268981
OBJECTIVES: Recurrent pancreatitis is considered a rare manifestation of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction; this case series highlights that pancreatitis can be a presenting symptoms of cystic fibrosis (CF) or a CFTR-related disorder (CFTR-RD). METHODS: Retrospective review of patients younger than 30 years diagnosed as having acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP) and subsequently diagnosed as having CF or CFTR-RD. RESULTS: Among 18 patients, median time from diagnosis of ARP/CP to diagnosis of CF was 0.4 years (range, 0-33 years). Eight were classified as having CF by elevated sweat chloride testing (SCT). Five had intermediate SCT (30-59 mmol/L) with 2 pathogenic mutations. Five had CFTR-RD with intermediate SCT and 0 to 1 pathogenic mutations. Eight patients (44%) had exocrine pancreatic insufficiency, and pancreatic fluid collections were more common in this group. Based on the CFTR mutation, 6 patients were eligible for CFTR potentiator therapy, although none received it during the study period. Nine of the 18 had ≥1 other likely CF manifestations, including sinusitis (33%), nasal polyps (11%), pneumonia (22%), and gallbladder disease (22%). CONCLUSIONS: Cystic fibrosis or CFTR-RD can present as ARP/CP. Complete diagnostic testing for CFTR-RD in patients with ARP/CP will broaden treatment options and help to identify comorbid illness.
doi: https://doi.org/10.1097/MPA.0000000000001350
- Epithelial Inclusions in Gallbladder May Mimic Parasite Infection
American journal of clinical pathology 2019 Aug;152(3):399-402
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31189015
doi: https://doi.org/10.1093/ajcp/aqz054
- Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study
The lancet. Gastroenterology & hepatology 2019 Aug;4(8):611-621
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31109808
BACKGROUND: This study aimed to assess the safety and tolerability of the immune checkpoint inhibitor nivolumab, as monotherapy or combined with chemotherapy, in Japanese patients with biliary tract cancer. METHODS: This multicentre, open-label, phase 1 trial was done at four cancer centres in Japan. Eligible patients were aged 20-79 years, had biliary tract adenocarcinoma (intrahepatic bile duct cancer, extrahepatic bile duct cancer, gallbladder cancer, or ampullary cancer), Eastern Cooperative Oncology Group performance status 0 or 1, adequate hepatic, renal, and haematological function, and tumour tissue samples for PD-L1 expression analysis. Patients with unresectable or recurrent biliary tract cancer that was refractory or intolerant to gemcitabine-based treatment regimens received nivolumab monotherapy (240 mg every 2 weeks [monotherapy cohort]). Chemotherapy-naive patients with unresectable or recurrent biliary tract cancer received nivolumab (240 mg every 2 weeks) and cisplatin (25 mg/m2) plus gemcitabine (1000 mg/m2) chemotherapy (combined therapy cohort). The primary objective was to assess tolerability and safety. The primary objective was assessed in the safety population of all patients who had received at least one dose of nivolumab. This study is registered with www.clinicaltrials.jp, number JapicCTI-153098, and follow-up is ongoing. FINDINGS: 30 patients were enrolled into each cohort between Jan 13, 2016, and April 19, 2017. Data cutoff was Aug 31, 2017. In the monotherapy cohort, the most frequently reported treatment-related adverse events were decreased appetite (five [17%]), malaise (four [13%]), and pruritus (four [13%]). Grade 3-4 treatment-related adverse events were reported by three (10%) patients (rash, maculopapular rash, and amylase increase) and treatment-related serious adverse events were reported by one (3%) patient (pleurisy). In the combined therapy cohort, the most frequently reported treatment-related adverse events were neutrophil count decrease (any grade 25 [83%]; grade 3-4 in 23 [77%] patients) and platelet count decrease (any grade 25 [83%] of 30; grade 3-4 in 15 [50%] patients). Six (20%) patients reported 11 treatment-related serious adverse events (platelet count decrease [three patients], febrile neutropenia [two patients], neutrophil count decrease, anaemia, anaphylactic reaction, decreased appetite, pyrexia, and myocarditis [one patient each]). In the monotherapy cohort, median overall survival was 5·2 months (90% CI 4·5-8·7), median progression-free survival was 1·4 months (90% CI 1·4-1·4), and one of 30 patients had an objective response. In the combined therapy cohort, median overall survival was 15·4 months (90% CI 11·8-not estimable), median progression-free survival was 4·2 months (90% CI 2·8-5·6), and 11 of 30 patients had an objective response. INTERPRETATION: Nivolumab had a manageable safety profile and signs of clinical activity in patients with unresectable or recurrent biliary tract cancer. This initial assessment of nivolumab for the treatment of advanced biliary tract cancer provides supportive evidence for future larger randomised studies of nivolumab in this difficult to treat cancer. FUNDING: Ono Pharmaceutical Co Ltd and Bristol-Myers Squibb Inc.
doi: https://doi.org/10.1016/S2468-1253(19)30086-X
- Detection of NRG1 Gene Fusions in Solid Tumors
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Aug;25(16):4966-4972
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30988082
PURPOSE: NRG1 gene fusions are rare but potentially actionable oncogenic drivers that are present in some solid tumors. Details regarding the incidence of these gene rearrangements are lacking. Here, we assessed the incidence of NRG1 fusions across multiple tumor types and described fusion partners. EXPERIMENTAL DESIGN: Tumor specimens submitted for molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory and that underwent fusion testing by anchored multiplex PCR for targeted RNA sequencing were retrospectively identified. The overall and tumor-specific incidence was noted, as was the specific fusion partner. RESULTS: Out of 21,858 tumor specimens profiled from September 2015 to December 2018, 41 cases (0.2%) harbored an NRG1 fusion. Multiple fusion partners were identified. Fusion events were seen across tumor types. The greatest incidence was in non-small cell lung cancer (NSCLC, 25), though this represented only 0.3% of NSCLC cases tested. Other tumor types harboring an NRG1 fusion included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer. CONCLUSIONS: NRG1 fusions can be detected at a low incidence across multiple tumor types with significant heterogeneity in fusion partner.See related commentary by Dimou and Camidge, p. 4865.
doi: https://doi.org/10.1158/1078-0432.CCR-19-0160
- Gallbladder Papilloma in a Child Unmasking Metachromatic Leukodystrophy: A Case Report With Review of Literature
Fetal and pediatric pathology 2019 Aug;38(4):345-351
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30912695
Background: Metachromatic leukodystrophy (MLD) is a lipid storage disease characterized the accumulation of sulfatides in different viscera including the gallbladder. Case report: A 2-year-old girl had upper right quadrant lesion that was preoperatively thought to be a biliary cystadenoma. Histologically, the gallbladder lesion was a tubulo-villous papilloma with multiple foci of papillary mucosal hyperplasia. Many storage histiocytes containing metachromatic granules, characteristic of MLD, were present in the tips of the papillae. MLD was later confirmed by enzyme studies. Conclusion: Gallbladder papilloma can be the presenting feature of MLD.
doi: https://doi.org/10.1080/15513815.2019.1588442
- Incidental Hepatic Tissue Obtained via Routine Cholecystectomy
International journal of surgical pathology 2019 Aug;27(5):499-505
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30520351
Background. The hepatic tissue that may occupy specimens from routine cholecystectomies has yet to be studied. Our objectives were to determine the prevalence of hepatic tissue obtained at routine cholecystectomy, to determine whether such hepatic tissue can histologically withstand technical artifacts commonly associated with cholecystectomy, and to determine whether examining such hepatic tissue has diagnostic utility. Materials and Methods. We retrospectively reviewed 50 specimens from routine cholecystectomies that were performed by surgeons who lacked knowledge of our study. All 50 specimens were grossed according to standard protocol, with only limited, nontargeted sampling of the rough nonperitonealized margin, and were received without fixative. Results. Twelve specimens (24.0%) contained hepatic tissue. The hepatic tissue measured up to 44.5-mm long and 1.8-mm wide and contained up to 11 complete portal tracts. Hepatic tissue in 3 specimens satisfied criteria for adequacy established for core biopsies based on number of portal tracts or size. Despite cautery and delayed fixation, all hepatic tissue had surprisingly well-preserved histology. Pathologic findings included nonalcoholic fatty liver disease, von Meyenburg complex, chronic cholestasis, and senescence. Conclusions. The hepatic tissue that accompanies specimens from routine cholecystectomies may be relatively common, can be large, is well preserved, and can harbor diagnostically useful information.
doi: https://doi.org/10.1177/1066896918817374
- Efficacy and Safety of Eluxadoline in Patients With Irritable Bowel Syndrome With Diarrhea Who Report Inadequate Symptom Control With Loperamide: RELIEF Phase 4 Study
The American journal of gastroenterology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31356229
OBJECTIVES: Irritable bowel syndrome with diarrhea (IBS-D) is a functional gastrointestinal disorder with limited effective treatment options. We evaluated the efficacy and safety of eluxadoline in patients with IBS-D who reported inadequate symptom control with prior loperamide. METHODS: Three hundred forty-six adults with IBS-D (Rome III criteria) were randomly assigned to placebo or eluxadoline 100 mg twice daily for 12 weeks. Patients recorded daily IBS-D symptoms, including worst abdominal pain (WAP) and stool consistency (through Bristol Stool Scale). The primary endpoint was proportion of composite responders, defined as patients who met daily composite response criteria (≥40% WAP improvement and <5 Bristol Stool Scale score) for at least 50% of treatment days, and recorded ≥60 days of diary entries over the 12-week period. RESULTS: Over 12 weeks, a significantly greater proportion of eluxadoline patients achieved the primary composite responder endpoint compared to placebo (22.7% vs 10.3%, P = 0.002), and component endpoints of improvements in stool consistency (27.9% vs 16.7%, P = 0.01) and WAP (43.6% vs 31.0%, P = 0.02). Additionally, a greater proportion of eluxadoline patients met the composite responder endpoint assessed at monthly intervals compared to placebo (weeks 1-4: 14.0% vs 6.9%, P = 0.03; weeks 5-8: 26.7% vs 14.9%, P = 0.006; weeks 9-12: 30.8% vs 16.7%, P = 0.002). Rates of adverse events were comparable in both groups (37.4% vs 35.3%); no treatment-related serious adverse event, cases of sphincter of Oddi spasm, or pancreatitis were reported. DISCUSSION: Eluxadoline appears safe and effective for treating IBS-D symptoms in patients with an intact gallbladder reporting inadequate relief with prior loperamide use.
doi: https://doi.org/10.14309/ajg.0000000000000327
- [Tumor-suspected focal lesion on the renal hilus]
Der Pathologe 2019 Sep;40(5):546-547
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31240450
Mucosal structures of a non-neoplastic organ can result in a pitfall diagnosis of adenocarcinoma in the case of a wrong correlation with other organs, in this case caused by an adherent gallbladder to the hilar structures of the right kidney. Clinical and radiological data are absolutely crucial for a correct classification.
doi: https://doi.org/10.1007/s00292-019-0621-4
- Colorectal metastasis to the gallbladder mimicking a primary gallbladder malignancy: histopathological and molecular characteristics
Histopathology 2019 Sep;75(3):394-404
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31044440
AIMS: Outcomes of colorectal cancer (CRC) treatment and survival have steadily improved during the past decades, accompanied by an increased risk of developing second primary tumours and metastatic tumours at unusual sites. Metastatic CRC can show mucosal colonisation, thereby mimicking a second primary tumour. This potential confusion could lead to incorrect diagnosis and consequently inadequate treatment of the patient. The aim of this study was to differentiate between metastatic CRC and a second primary (gallbladder cancer, GBC) using a combination of standard histopathology and molecular techniques. METHODS AND RESULTS: Ten consecutive patients with both CRC and GBC were identified in our region using the Dutch National Pathology Archive (PALGA). Two patients served as negative controls. Histology of GBC was reviewed by nine pathologists. A combination of immunohistochemistry, microsatellite analysis, genomewide DNA copy number analysis and targeted somatic mutation analysis was used to aid in differential diagnosis. In two patients, CRC and GBC were clonally related, as confirmed by somatic mutation analysis. For one case, this was confirmed by genomewide DNA copy number analysis. However, in both cases, pathologists initially considered the GBC as a second primary tumour. CONCLUSIONS: Metastatic CRC displaying mucosal colonisation is often misinterpreted as a second primary tumour. A combination of traditional histopathology and molecular techniques improves this interpretation, and lowers the risk of inadequate treatment.
doi: https://doi.org/10.1111/his.13892
- IL-33 overexpression in gallbladder cancers associated with pancreatobiliary maljunction
Histopathology 2019 Sep;75(3):365-375
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30882917
AIMS: To investigate whether genetic or inflammatory pro-oncogenic factors are relevant to the increased risk of gallbladder cancers in patients with pancreaticobiliary maljunction (PBM). METHODS AND RESULTS: Mutations in KRAS exon 2 were examined by a highly sensitive, droplet digital PCR platform using surgically resected specimens of PBM-associated (n = 31) and non-associated gallbladder cancers (n = 49). The tissue expression of IL-6 and IL-33, which are suspected to promote biliary carcinogenesis, was analysed by quantitative real-time PCR and in-situ hybridisation. The incidence of KRAS mutations was similarly low in PBM-associated (five of 32 cases; 16%) and non-associated cancers (four of 49 cases; 8%) (P = 0.272). The tissue expression of IL-33 mRNA, but not IL-6 mRNA, was significantly higher in PBM-associated gallbladder cancers than in gallbladder cancers without PBM (P = 0.004). A similar degree of IL-33 overexpression was also observed in the background non-cancerous mucosa in cases of PBM-associated gallbladder cancers, and was significantly greater than that in PBM cases with cholecystitis alone (P < 0.001). The results of in-situ hybridisation indicated that the source of IL-33 production in PBM-associated carcinomas was the endothelium, cancer cells and non-neoplastic biliary epithelium. In a combined PBM-associated and non-associated cohort, IL-33 overexpression in gallbladder cancers correlated with less aggressive features (e.g. a lower pT stage and longer overall survival), similar to recently reported findings on large-duct cholangiocarcinomas. CONCLUSIONS: KRAS mutations do not appear to be associated with a high risk of malignancy in PBM, while IL-33 overexpression may provide a pro-oncogenic microenvironment in the gallbladder mucosa of patients with PBM.
doi: https://doi.org/10.1111/his.13863
- Second-line chemotherapy in advanced biliary cancers: A retrospective, multicenter analysis of outcomes
Cancer 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31454426
BACKGROUND: Although gemcitabine plus platinum chemotherapy is the established first-line regimen for advanced biliary cancer (ABC), there is no standard second-line therapy. This study evaluated current practice and outcomes for second-line chemotherapy in patients with ABC across 3 US academic medical centers. METHODS: Institutional registries were reviewed to identify patients who had received second-line chemotherapy for ABC from April 2010 to March 2015 along with their demographics, diagnoses and staging, treatment histories, and clinical outcomes. Overall survival from the initiation of second-line chemotherapy (OS2) was estimated with Kaplan-Meier methods. RESULTS: This study identified 198 patients with cholangiocarcinoma (intrahepatic [61.1%] or extrahepatic [14.1%]) or gallbladder carcinoma (24.8%); 52% received at least 3 lines of systemic chemotherapy. The median OS2 was 11 months (95% confidence interval [CI], 8.8-13.1 months). The median OS2 for patients with intrahepatic cholangiocarcinoma was 13.4 months (95% CI, 10.7-17.8 months), which was longer than that for patients with extrahepatic cholangiocarcinoma (6.8 months; 95% CI, 5-10.6 months) or gallbladder carcinoma (9.4 months; 95% CI, 7.2-12.3 months; P = .018). The median time to second-line treatment failure was 2.2 months (95% CI, 1.8-2.7 months), and it was similar across tumor locations (P = .60). CONCLUSIONS: In this large cohort of patients with ABC treated across 3 academic medical centers after the failure of first-line chemotherapy, the time to treatment failure on standard therapies was short, although the median OS2 was longer than has been reported previously, and more than half of the patients received additional lines of treatment. This multicenter collaboration represents the largest cohort studied to date of second-line chemotherapy for ABC and provides a contemporary benchmark for future clinical trials.
doi: https://doi.org/10.1002/cncr.32463
- Non Syndromic Paucity of Interlobular Bile Ducts in Children - A Clinicopathological Study
Fetal and pediatric pathology 2019 Aug;():1-17
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31437071
Background: Non syndromic paucity of interlobular bile ducts (NS-PILBD) constitutes a miniscule of infantile cholestasis. Method: Clinical details, investigations, surgical findings, management and outcome of cases of NS-PILBD at liver biopsy were analyzed. Specific histopathological features including bile duct to portal tract ratio were studied. Results: Eighteen cases (1993-2013) are detailed. Clinical presentation and investigations were similar to biliary atresia. Hepatic scintigraphy showed no gut excretion in 13/18 and operative cholangiogram was normal in all. Liver biopsy showed a median Scheuer fibrosis stage of 2, the mean bile duct/portal tract ratio was 0.29. The average age at last follow up of twelve cases was 54.9 months . Ten were asymptomatic and anicteric, the liver function tests had normalized over 3-15 months. Conclusion: Histopathology differentiated NS-PILBD from other causes of infantile cholestasis .The idiopathic form generally had a favorable long term outcome with medical management.
doi: https://doi.org/10.1080/15513815.2019.1652376
- Emphysematous Cholecystitis
The New England journal of medicine 2019 Aug;381(8):e14
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31433924
doi: https://doi.org/10.1056/NEJMicm1814551
- Fragile X mental retardation protein protects against tumour necrosis factor-mediated cell death and liver injury
Gut 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31409605
OBJECTIVE: The Fragile X mental retardation (FMR) syndrome is a frequently inherited intellectual disability caused by decreased or absent expression of the FMR protein (FMRP). Lack of FMRP is associated with neuronal degradation and cognitive dysfunction but its role outside the central nervous system is insufficiently studied. Here, we identify a role of FMRP in liver disease. DESIGN: Mice lacking Fmr1 gene expression were used to study the role of FMRP during tumour necrosis factor (TNF)-induced liver damage in disease model systems. Liver damage and mechanistic studies were performed using real-time PCR, Western Blot, staining of tissue sections and clinical chemistry. RESULTS: Fmr1null mice exhibited increased liver damage during virus-mediated hepatitis following infection with the lymphocytic choriomeningitis virus. Exposure to TNF resulted in severe liver damage due to increased hepatocyte cell death. Consistently, we found increased caspase-8 and caspase-3 activation following TNF stimulation. Furthermore, we demonstrate FMRP to be critically important for regulating key molecules in TNF receptor 1 (TNFR1)-dependent apoptosis and necroptosis including CYLD, c-FLIPS and JNK, which contribute to prolonged RIPK1 expression. Accordingly, the RIPK1 inhibitor Necrostatin-1s could reduce liver cell death and alleviate liver damage in Fmr1null mice following TNF exposure. Consistently, FMRP-deficient mice developed increased pathology during acute cholestasis following bile duct ligation, which coincided with increased hepatic expression of RIPK1, RIPK3 and phosphorylation of MLKL. CONCLUSIONS: We show that FMRP plays a central role in the inhibition of TNF-mediated cell death during infection and liver disease.
doi: https://doi.org/10.1136/gutjnl-2019-318215
- Decompressive laparotomy for abdominal compartment syndrome resulting from severe acute pancreatitis: a case report
BMC gastroenterology 2019 Aug;19(1):141
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31395017
BACKGROUND: Abdominal compartment syndrome (ACS) is associated with mortality in patients with critical illness such as severe acute pancreatitis, but it remains unclear whether decompressive laparotomy for ACS can improve the prognosis of patients. CASE PRESENTATION: A woman in her 60s visited our hospital because of upper abdominal pain. On the basis of her laboratory data and abdominal contrast-enhanced computed tomography findings, acute gallstone pancreatitis was diagnosed. She underwent endoscopic sphincterotomy for the removal of the common bile duct stone. Then, a drainage tube was placed in the bile duct. However, on the 5th hospital day, her intra-abdominal pressure increased to 22 mmHg and renal dysfunction was observed, which led to the diagnosis of ACS. As intensive medical treatments did not improve her ACS, she underwent decompressive laparotomy on the 9th hospital day. Postoperatively, her laboratory data and intravesical pressure improved, and she was discharged from the hospital after abdominal closure, continuous drainage, and antibiotic therapy. CONCLUSION: As the effectiveness of decompressive laparotomy for ACS has not been established, this treatment indication remains controversial. Decompressive laparotomy is considered useful for the management of ACS, if it is performed at an appropriate time, as in the present case.
doi: https://doi.org/10.1186/s12876-019-1059-0
- Classification of the cystic duct patterns and endoscopic transpapillary cannulation of the gallbladder to prevent post-ERCP cholecystitis
BMC gastroenterology 2019 Aug;19(1):139
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31382888
BACKGROUND: Endoscopic transpapillary cannulation of the gallbladder is useful but challenging. This study aimed to investigate cystic duct anatomy patterns, which may guide cystic duct cannulation. METHODS: A total of 226 patients who underwent endoscopic transpapillary cannulation of the gallbladder were analyzed retrospectively. RESULTS: According to the cystic duct take-off, 226 cystic duct patterns were divided into 3 patterns: Type I (193, 85.4%), located on the right and angled up; Type II (7, 3.1%), located on the right and angled down; and Type III (26, 11.5%), located on the left and angled up. Type I was further divided into three subtypes: Line type, S type (S1, not surrounding the common bile duct; S2, surrounding the common bile duct), and α type (α1, forward α; α2, reverse α). Types I and III cystic ducts were easier to be cannulated with a higher success rate (85.1 and 86.4%, respectively) compared with Type II cystic duct (75%) despite no statistically significant difference. The reasons for the failure of gallbladder cannulation included invisible cyst duct take-off, severe cyst duct stenosis, impacted stones in cyst duct or neck of the gallbladder, sharply angled cyst duct, and markedly dilated cyst duct with the tortuous valves of Heister. CONCLUSION: Classification of cystic duct patterns was helpful in guiding endoscopic transpapillary gallbladder cannulation.
doi: https://doi.org/10.1186/s12876-019-1053-6
- Liver biopsy in primary biliary cholangitis: is sinusoidal fibrosis the missing key?
Journal of clinical pathology 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31371396
AIMS: The role of liver biopsy in primary biliary cholangitis (PBC) is controversial, as is the optimal method of histological assessment. We compared the Ludwig and Ishak systems and three components of the Japanese (Nakanuma) staging system to evaluate their clinical and biochemical correlations and prognostic value. METHODS: We reviewed biopsies from 106 patients with PBC, derived from a previous trial of colchicine therapy with 24-34 years’ follow-up, following which five clinical outcomes were evaluated: hepatic decompensation, cholestatic PBC death/liver transplant, portal hypertensive PBC death, all PBC deaths and overall survival. RESULTS: Ludwig and Ishak stages correlated well with prognostically significant parameters, including serum bilirubin, and both Mayo and Child Scores. Serum aspartate aminotransferase correlated with interface hepatitis (IFH), and alkaline phosphatase with orcein deposition, bile duct (BD) loss and cholestasis. Ludwig correlated with all five clinical outcomes, while Ishak stage was only significantly correlated with two. While sinusoidal fibrosis, orcein deposition, BD loss and cholestasis all predicted hepatic death/transplant, after correction for Mayo Score, the only histological parameters predictive of clinical outcomes were IFH (associated with two) and sinusoidal fibrosis (associated with all five). CONCLUSION: Liver biopsy is required in the diagnosis of around 20% of patients with PBC. The Ludwig system is of more prognostic value than both Ishak and any of the three individual components of the Nakanuma staging system, but the major histological parameter providing independent prognostic value beyond the Mayo Score is sinusoidal fibrosis.
doi: https://doi.org/10.1136/jclinpath-2019-205958
- Intrahepatic cholestasis: suggested future investigations
Lancet (London, England) 2019 08;394(10198):e17
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31272691
doi: https://doi.org/10.1016/S0140-6736(19)31391-1
- Intrahepatic cholestasis: suggested future investigations - Authors’ reply
Lancet (London, England) 2019 08;394(10198):e18
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31272690
doi: https://doi.org/10.1016/S0140-6736(19)31389-3
- British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis
Gut 2019 08;68(8):1356-1378
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31154395
These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.
doi: https://doi.org/10.1136/gutjnl-2018-317993
- Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study
The lancet. Gastroenterology & hepatology 2019 Aug;4(8):611-621
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31109808
BACKGROUND: This study aimed to assess the safety and tolerability of the immune checkpoint inhibitor nivolumab, as monotherapy or combined with chemotherapy, in Japanese patients with biliary tract cancer. METHODS: This multicentre, open-label, phase 1 trial was done at four cancer centres in Japan. Eligible patients were aged 20-79 years, had biliary tract adenocarcinoma (intrahepatic bile duct cancer, extrahepatic bile duct cancer, gallbladder cancer, or ampullary cancer), Eastern Cooperative Oncology Group performance status 0 or 1, adequate hepatic, renal, and haematological function, and tumour tissue samples for PD-L1 expression analysis. Patients with unresectable or recurrent biliary tract cancer that was refractory or intolerant to gemcitabine-based treatment regimens received nivolumab monotherapy (240 mg every 2 weeks [monotherapy cohort]). Chemotherapy-naive patients with unresectable or recurrent biliary tract cancer received nivolumab (240 mg every 2 weeks) and cisplatin (25 mg/m2) plus gemcitabine (1000 mg/m2) chemotherapy (combined therapy cohort). The primary objective was to assess tolerability and safety. The primary objective was assessed in the safety population of all patients who had received at least one dose of nivolumab. This study is registered with www.clinicaltrials.jp, number JapicCTI-153098, and follow-up is ongoing. FINDINGS: 30 patients were enrolled into each cohort between Jan 13, 2016, and April 19, 2017. Data cutoff was Aug 31, 2017. In the monotherapy cohort, the most frequently reported treatment-related adverse events were decreased appetite (five [17%]), malaise (four [13%]), and pruritus (four [13%]). Grade 3-4 treatment-related adverse events were reported by three (10%) patients (rash, maculopapular rash, and amylase increase) and treatment-related serious adverse events were reported by one (3%) patient (pleurisy). In the combined therapy cohort, the most frequently reported treatment-related adverse events were neutrophil count decrease (any grade 25 [83%]; grade 3-4 in 23 [77%] patients) and platelet count decrease (any grade 25 [83%] of 30; grade 3-4 in 15 [50%] patients). Six (20%) patients reported 11 treatment-related serious adverse events (platelet count decrease [three patients], febrile neutropenia [two patients], neutrophil count decrease, anaemia, anaphylactic reaction, decreased appetite, pyrexia, and myocarditis [one patient each]). In the monotherapy cohort, median overall survival was 5·2 months (90% CI 4·5-8·7), median progression-free survival was 1·4 months (90% CI 1·4-1·4), and one of 30 patients had an objective response. In the combined therapy cohort, median overall survival was 15·4 months (90% CI 11·8-not estimable), median progression-free survival was 4·2 months (90% CI 2·8-5·6), and 11 of 30 patients had an objective response. INTERPRETATION: Nivolumab had a manageable safety profile and signs of clinical activity in patients with unresectable or recurrent biliary tract cancer. This initial assessment of nivolumab for the treatment of advanced biliary tract cancer provides supportive evidence for future larger randomised studies of nivolumab in this difficult to treat cancer. FUNDING: Ono Pharmaceutical Co Ltd and Bristol-Myers Squibb Inc.
doi: https://doi.org/10.1016/S2468-1253(19)30086-X
- Evaluation of histologic changes in the livers of patients with early and late hepatic artery thrombosis
Human pathology 2019 Aug;90():8-13
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31075300
Hepatic artery thrombosis (HAT) following orthotopic liver transplantation (OLT) can cause hepatic parenchymal necrosis and ischemic cholangiopathy. This study investigates additional histologic features that may suggest HAT in post-OLT liver specimens. For 94 liver specimens (explanted allografts and biopsies) from patients with a clinical or pathologic diagnosis of HAT, we recorded length of time between OLT and procedure, categorizing cases into early HAT (;≤30 days since OLT) and late HAT (>30 days since OLT). Common histologic findings in HAT included lobular necrosis (60 cases, 64%), portal inflammation (68 cases, 72%), ductular reaction (73 cases, 78%), lobular cholestasis (70 cases, 74%), and bile-tinged macrophages (40 cases, 43%). Ductular cholestasis was seen in 30 cases (32%); 10 of those patients were clinically septic. Bile in veins was seen in 16 (17%) cases and arteritis in 6 (6%) cases. Findings more common in resection than biopsy specimens included lobular necrosis (P < .0001), hemorrhage (P = .0044), ductular cholestasis (P = .0003), and bile-tinged macrophages (P < .0001). Lobular necrosis was more common in early HAT (P = .0002), and ductular reaction (P = .006) and bile in veins (P = .03) were more common in late HAT. Histologic changes in HAT vary based on specimen type and whether HAT is early or late. In late HAT, biliary injury might occur after a prolonged period of ischemia, with subsequent bile duct necrosis, bile in veins, and remodeling (eg, ductular reaction). Bile in veins is an unusual finding that may occur in HAT, although it can be seen in bile infarcts from other causes.
doi: https://doi.org/10.1016/j.humpath.2019.04.019
- Intraoperative Air Leak Test to Prevent Bile Leak After Right Posterior Sectionectomy with En Bloc Diaphragm Resection for Metastatic Teratoma
Annals of surgical oncology 2019 Aug;26(8):2579
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31065963
BACKGROUND: The intraoperative air cholangiogram, or “air leak test” (ALT), at the time of hepatectomy can significantly reduce the rates of bile leak and symptomatic fluid collection after high-risk procedures.1,2 Because a bile leak in the setting of an en bloc diaphragm resection and mesh reconstruction would be a particularly dreaded complication, this video shows the technique for resection, reconstruction, and ALT. PRESENTATION: The video presents the case of a 29-year-old woman who had metastatic teratoma with an 8 × 7-cm liver metastasis in segment 7 and diaphragm invasion to the level of the right hepatic vein. OPERATION: The authors performed a formal right posterior sectionectomy with en bloc diaphragm resection. The 12 × 8-cm diaphragmatic defect was reconstructed using biologic mesh (Surgimend, Integra LifeSciences, Plainsboro, NJ). An intraoperative ALT (air injection into the cystic duct with finger compression of the distal bile duct) identified several areas of bubbles from biliary radicles on the cut surface of the liver, which were ligated with 4-0 polypropylene. The ALT was repeated until no bubbles remained. Because no evidence of bubbles was observed, no surgical drain was needed. The patient did well postoperatively with no complications. CONCLUSION: In cases of combined liver and diaphragmatic resection, prevention of bile leak, with subsequent contamination of the diaphragm repair and even the thoracic cavity, is particularly vital. An easily replicated intraoperative air leak test can mitigate the risk of bile leak and organ-space infection, as well as associated sequelae on quality of life, return to intended oncologic therapy, and oncologic outcomes.
doi: https://doi.org/10.1245/s10434-019-07410-y
- Microbiota as a cornerstone in the development of primary sclerosing cholangitis: paving the path for translational diagnostic and therapeutic approaches
Gut 2019 08;68(8):1353-1355
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31028154
doi: https://doi.org/10.1136/gutjnl-2019-318487
- Spontaneous Pneumobilia and Hematemesis
Gastroenterology 2019 08;157(2):e8-e9
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30959037
doi: https://doi.org/10.1053/j.gastro.2019.03.053
- Liver Masses
Gastroenterology 2019 08;157(2):e3-e4
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30959031
doi: https://doi.org/10.1053/j.gastro.2019.03.057
- Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis
Gut 2019 08;68(8):1477-1492
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30872395
OBJECTIVE: There is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut-liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2-/-) model resembling human primary sclerosing cholangitis (PSC). DESIGN: Male Mdr2-/-, Mdr2-/- crossed with hepatocyte-specific deletion of caspase-8 (Mdr2-/- /Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2-/- -associated intestinal dysbiosis was studied by microbiota transfer experiments. RESULTS: Mdr2-/- mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut-liver axis. Intestinal dysbiosis in Mdr2-/- mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2-/- microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature. CONCLUSIONS: MDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.
doi: https://doi.org/10.1136/gutjnl-2018-316670
- Statin use and reduced risk of biliary tract cancers in the UK Clinical Practice Research Datalink
Gut 2019 08;68(8):1458-1464
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30448774
OBJECTIVE: To evaluate the association between statin use and risk of biliary tract cancers (BTC). DESIGN: This is a nested case-control study conducted in the UK Clinical Practice Research Datalink. We included cases diagnosed with incident primary BTCs, including cancers of the gall bladder, bile duct (ie, both intrahepatic and extrahepatic cholangiocarcinoma), ampulla of Vater and mixed type, between 1990 and 2017. For each case, we selected five controls who did not develop BTCs at the time of case diagnosis, matched by sex, year of birth, calendar time and years of enrolment in the general practice using incidence density sampling. Exposures were defined as two or more prescription records of statins 1 year prior to BTC diagnosis or control selection. ORs and 95% CIs for associations between statins and BTC overall and by subtypes were estimated using conditional logistic regression, adjusted for relevant confounders. RESULTS: We included 3118 BTC cases and 15 519 cancer-free controls. Current statin use versus non-use was associated with a reduced risk of all BTCs combined (adjusted OR=0.88, 95% CI 0.79 to 0.98). The reduced risks were most pronounced among long-term users, as indicated by increasing number of prescriptions (ptrend=0.016) and cumulative dose of statins (ptrend=0.008). The magnitude of association was similar for statin use and risk of individual types of BTCs. The reduced risk of BTCs associated with a record of current statin use versus non-use was more pronounced among persons with diabetes (adjusted OR=0.72, 95% CI 0.57 to 0.91). Among non-diabetics, the adjusted OR for current statin use versus non-use was 0.91 (95% CI 0.81 to 1.03, pheterogeneity=0.007). CONCLUSION: Compared with non-use of statins, current statin use is associated with 12% lower risk of BTCs; no association found with former statin use. If replicated, particularly in countries with a high incidence of BTCs, our findings could pave the way for evaluating the value of statins for BTC chemoprevention.
doi: https://doi.org/10.1136/gutjnl-2018-317504
- Oral vancomycin induces clinical and mucosal remission of colitis in children with primary sclerosing cholangitis-ulcerative colitis
Gut 2019 08;68(8):1533-1535
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=30131321
doi: https://doi.org/10.1136/gutjnl-2018-316599
- Clinical value of DPOC for detecting and removing residual common bile duct stones (video)
BMC gastroenterology 2019 Jul;19(1):135
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31349795
BACKGROUND: This study aims to evaluate the efficacy and safety of detecting and removing residual common bile duct stones (CBDS) using direct peroralcholangioscopy (DPOC) after performing endoscopic retrograde cholangiopancreatography (ERCP) for stone retrieval. METHODS: From January 5, 2017 to December 27, 2017, a total of 164 cases of choledocholithiasis were treated by ERCP for stone retrieval. According to the inclusion and exclusion criteria, the remaining 79 cases (39 males; mean age: 63.3 years old, range: 52-79 years old) were enrolled in the present study. The maximum transverse stone diameter was 6-15 mm (12.7 ± 4.2 mm), as determined by ERCP. Furthermore, there were 57 cases of multiple stones (number of stones: two in 41 cases, three in nine cases, and ≥ 4 in seven cases), 13 cases of post-mechanical lithotripsy, and nine cases of broken stones. RESULTS: The overall success rate of DPOC was 94.9% (75/79). Furthermore, 18.7%(14/75) of cases were directly inserted, 72%(54/75) of cases required guide wire assistance, and 9.3%(7/75) of cases were successfully inserted with overtube assistance. The average insertion time was 7-17 min (4.9 ± 2.9 min). Residual stones were detected in 19 cases (25.3%), and all of which were < 5 mm in diameter. Moreover, five cases of formed stones were removed by basket and balloon catheter, while the remaining cases were cleaned after irrigation and suction. There were no serious complications. CONCLUSION: DPOC is safe and effective for both the detection and removal of residual CBDS after conventional ERCP.
doi: https://doi.org/10.1186/s12876-019-1045-6
- Immunoglobulin G4-related hepatobiliary disease
Seminars in diagnostic pathology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31358425
Immunoglobuline G4-related disease (IgG4-RD) is a systemic disease that can involve virtually any organs including the biliary tract and liver. The biliary tract involvement of IgG4-RD is known as IgG4-sclerosing cholangitis (IgG4-SC) and may or may not present with an inflammatory pseudotumor. Large bile ducts such as extrahepatic, hilar, and perihilar ducts are typically affected and demonstrate marked bile duct wall thickening and develop strictures. Histologically, the involved ducts show transmural dense lymphoplasmacytic infiltrates with storiform fibrosis extending into peribiliary glands and periductal soft tissue. The luminal epithelium is usually preserved. Tissue eosinophilia and obliterative phlebitis are also frequently noted. Liver biopsy findings of IgG4-SC are heterogeneous and rather nonspecific, but two features specific to IgG4-SC have been described: >10 IgG4-positive plasma cell/HPF and small portal-based fibroinflammatory nodules. Secondary changes, due to downstream bile duct obstruction are often appreciated. When considering the differential diagnosis, primary sclerosing cholangitis and cholangiocarcinoma are great clinical and histologic mimics of IgG4-SC. Liver involvement in IgG4-RD has not been well characterized and includes IgG4-hepatopathy and IgG4-related autoimmune hepatitis (AIH). IgG4-hepatopathy is a generic term covering hepatic lesions related to IgG4-RD and /or IgG4-SC. It includes primary liver parenchymal changes inherent to IgG4-RD, liver parenchymal involvement of IgG4-SC, and secondary changes related to IgG4-SC. IgG4-related AIH is characterized by clinical and histologic features of classical AIH but with prominent (>10/HPF) IgG4-positive plasma cells. It is unclear whether this represents a hepatic manifestation of IgG4-RD or a subset of AIH with increased IgG4-positive plasma cells at the present time. Synchronous or metachronous involvement of other organs, offers a clue to make this distinction. IgG4 immunohistochemistry has an important role in diagnosing IgG4-RD. But the diagnosis cannot be made solely based on the number of IgG4-positive plasma cells, and results need to be interpreted with caution as increased IgG4-positive plasma cells can be seen in other inflammatory conditions or even in malignancy.
doi: https://doi.org/10.1053/j.semdp.2019.07.007
- Checkpoint inhibitor-induced liver injury: A novel form of liver disease emerging in the era of cancer immunotherapy
Seminars in diagnostic pathology 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31358424
Liver injury triggered by immune checkpoint inhibitors has been increasingly seen in clinical practice, and the incidence is likely to rise further in the next several years because of expanded indications for cancer immunotherapy. Tissue damage driven by disrupted immune tolerance against self-antigens is called an immune-related adverse event (irAE). irAEs in the liver histologically presents panlobular hepatitis (∼70%), isolated central zonal necrosis (∼20%), primarily granulomatous hepatitis (∼5%), and other minor forms of tissue injury (∼5%). Infiltrating cells are mainly lymphocytes and occasional eosinophils. Unlike classic autoimmune hepatitis (AIH), plasma cell infiltration is not conspicuous. Immunostaining reveals a large number of CD8+ T lymphocytes and a markedly smaller number of CD4+ cells or CD20+ B lymphocytes. The unique CD3+/CD20+ and CD4+/CD8+ ratios shifted in favor of CD8+ cytotoxic T lymphocytes are helpful to discriminate irAEs from other conditions (e.g., AIH, idiosyncratic drug-induced liver injury). Another hepatobiliary manifestation of irAEs is sclerosing cholangitis clinically characterized by elevations of biliary enzymes, diffuse duct wall thickening, and duct dilatation. Lymphocytic infiltration can be observed by endoscopic biopsies from the thick extrahepatic bile ducts, and liver needle biopsies may also show severe lymphocytic cholangitis resembling primary biliary cholangitis. An important differential diagnosis of irAEs is previously asymptomatic or subclinical liver disease unmasked by cancer immunotherapy, which is often challenging and requires close clinicopathological correlations.
doi: https://doi.org/10.1053/j.semdp.2019.07.009
- Development of a Theranostic Convergence Bioradiopharmaceutical for Immuno-PET based Radioimmunotherapy of L1CAM in Cholangiocarcinoma Model
Clinical cancer research : an official journal of the American Association for Cancer Research 2019 Jul;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31337646
PURPOSE: Cholangiocarcinoma (CCA) is a malignancy of bile duct with a poor prognosis. Conventional chemotherapy and radiation therapy are generally ineffective and surgical resection is the only curative treatment for CCA. L1-cell adhesion molecule (L1CAM) has been known as a novel prognostic marker and therapeutic target for CCA. This study aimed to evaluate the feasibility of immuno-positron emission tomography (PET) imaging-based radioimmunotherapy using radiolabeled anti-L1CAM antibody in CCA xenograft model. EXPERIMENTAL DESIGN: We prepared a theranostic convergence bioradiopharmaceutical using chimeric anti-L1CAM antibody (cA10-A3) conjugated with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator and labeled with 64Cu or 177Lu and evaluated the immuno-PET or SPECT/CT imaging and biodistribution with 64Cu-/177Lu-cA10-A3 in various CCA xenograft models. Therapeutic efficacy and response monitoring were performed by 177Lu-cA10-A3 and 18F-FDG-PET, respectively, and immunohistochemistry was done by TUNEL and Ki-67. RESULTS: Radiolabeled cA10-A3 antibodies specifically recognized L1CAM in vitro, clearly visualized CCA tumors in immuno-PET and SPECT/CT imaging, and differentiated the L1CAM expression level in CCA xenograft models. 177Lu-cA10-A3 (12.95 MBq/100 μg) showed statistically significant reduction in tumor volumes (P < 0.05) and decreased glucose metabolism (P < 0.01). IHC analysis revealed 177Lu-cA10-A3 treatment increased TUNEL-positive and decreased Ki-67-positive cells, compared with saline, cA10-A3, or 177Lu-isotype. CONCLUSIONS: Anti-L1CAM immuno-PET imaging using 64Cu-cA10-A3 could be translated into the clinic for characterizing the pharmacokinetics and selecting pertinent patient for radioimmunotherapy. Radioimmunotherapy using 177Lu-cA10-A3 may provide survival benefit in L1CAM expressing CCA tumor. Theranostic convergence bioradiopharmaceutical strategy would be applied as an imaging biomarker based personalized medicine in L1CAM expressing CCA patients.
doi: https://doi.org/10.1158/1078-0432.CCR-19-1157
- Minimally Invasive Treatment for Severe Acute Pancreatitis With Superior Mesenteric Vein and Common Bile Duct Stenosis: A Case Report and Review of the Literature
Pancreas 2019 Sep;48(8):e61-e63
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425486
doi: https://doi.org/10.1097/MPA.0000000000001379
- Aryl Hydrocarbon Receptor Signaling Prevents Activation of Hepatic Stellate Cells and Liver Fibrogenesis in Mice
Gastroenterology 2019 09;157(3):793-806.e14
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31170413
BACKGROUND & AIMS: The role of aryl hydrocarbon receptor (AhR) in liver fibrosis is controversial because loss and gain of AhR activity both lead to liver fibrosis. The goal of this study was to investigate how the expression of AhR by different liver cell types, hepatic stellate cells (HSCs) in particular, affects liver fibrosis in mice. METHODS: We studied the effects of AhR on primary mouse and human HSCs, measuring their activation and stimulation of fibrogenesis using RNA-sequencing analysis. C57BL/6J mice were given the AhR agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 2-(1’H-indole-3’-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE); were given carbon tetrachloride (CCl4); or underwent bile duct ligation. We also performed studies in mice with disruption of Ahr specifically in HSCs, hepatocytes, or Kupffer cells. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, and immunoblotting. RESULTS: AhR was expressed at high levels in quiescent HSCs, but the expression decreased with HSC activation. Activation of HSCs from AhR-knockout mice was accelerated compared with HSCs from wild-type mice. In contrast, TCDD or ITE inhibited spontaneous and transforming growth factor β-induced activation of HSCs. Mice with disruption of Ahr in HSCs, but not hepatocytes or Kupffer cells, developed more severe fibrosis after administration of CCl4 or bile duct ligation. C57BL/6J mice given ITE did not develop CCl4-induced liver fibrosis, whereas mice without HSC AhR given ITE did develop CCl4-induced liver fibrosis. In studies of mouse and human HSCs, we found that AhR prevents transforming growth factor β-induced fibrogenesis by disrupting the interaction of Smad3 with β-catenin, which prevents the expression of genes that mediate fibrogenesis. CONCLUSIONS: In studies of human and mouse HSCs, we found that AhR prevents HSC activation and expression of genes required for liver fibrogenesis. Development of nontoxic AhR agonists or strategies to activate AhR signaling in HSCs might be developed to prevent or treat liver fibrosis.
doi: https://doi.org/10.1053/j.gastro.2019.05.066
- The Pathologic and Genetic Characteristics of the Intestinal Subtype of Intraductal Papillary Neoplasms of the Bile Duct
The American journal of surgical pathology 2019 Sep;43(9):1212-1220
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31166202
The present study aimed to identify the pathologic and genetic characteristics of intestinal subtype of intraductal papillary neoplasm of the bile duct (iIPNB) showing columnar cells with pseudostratified, cigar-shaped nuclei, and basophilic or amphophilic cytoplasm with the diffuse immunohistochemical expression of CK20 and/or CDX2. A total of 34 cases of iIPNB were pathologically examined according to their anatomic location (the bile duct) and were then compared with the intestinal subtype of intraductal papillary mucinous neoplasm (iIPMN) of the pancreas (n=22). Mutations of 26 somatic genes were examined in formalin-fixed paraffin-embedded tissue specimens from 21 cases of iIPNB using the TruSight Tumor 26 gene panel and next-generation sequencing. iIPNB cases were divided into intrahepatic (n=6) and extrahepatic (n=28) categories. Intrahepatic IPNBs showed a less-complicated villous-papillary pattern, while extrahepatic IPNBs showed a papillary pattern with tubular and/or villous components and predominant high-grade dysplasia with complicated architectures. MUC5AC was frequently and extensively expressed in intrahepatic iIPNBs and iIPMNs but not in extrahepatic iIPNBs. CD10 was frequently expressed in extrahepatic IPNBs but not in intrahepatic iIPNBs or iIPMN. Genetic mutations of TP53 and PIK3CA, which were infrequent or absent in iIPMNs, were frequently detected in extrahepatic iIPNBs, while KRAS and GNAS, which were commonly observed in iIPMNs, were frequently detected in intrahepatic iIPNBs. Intrahepatic iIPNBs showed villous-papillary growth with features reminiscent of iIPMNs, while extrahepatic iIPNBs showed papillary growth with tubular and/or villous components, complicated histology and variable differences from iIPMNs, suggesting differences in the tumorigenesis of iIPNBs along the biliary tree.
doi: https://doi.org/10.1097/PAS.0000000000001295
- Robotic Left Hepatectomy and Roux-en-Y Hepaticojejunostomy After Bile Duct Injury
Annals of surgical oncology 2019 Sep;26(9):2981-2984
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31147989
BACKGROUND: Bile duct injuries after cholecystectomy remain a major concern because their incidence has not changed through the years despite technical advances. This video presents a robotic left hepatectomy and Roux-en-Y hepaticojejunostomy as a treatment for a complex bile duct injury after laparoscopic cholecystectomy. METHODS: A 52-year-old man underwent laparoscopic cholecystectomy at another institution 8 years previously, which resulted in a bile duct injury. His postoperative period was complicated by jaundice and cholangitis. He was treated with endoscopic retrograde cholangiopancreatography and multiple endoprostheses for 3 years, after which the endoprostheses were removed, and he was sent to the authors’ institution. Computed tomography showed that the left liver had signs of disturbed perfusion and dilation of the left intrahepatic bile duct. The patient was asymptomatic and refused any further attempt at surgical correction of the lesion. He was accompanied for 5 years. Magnetic resonance imaging showed progressive atrophy of the left liver. Finally, 3 months before this writing, he presented with intermittent episodes of cholangitis. A multidisciplinary team decided to perform left hepatectomy with Roux-en-Y hepatojejunostomy via a robotic approach. The left liver was atrophied, and left hepatectomy was performed. Fluorescence imaging was used to identify the right bile duct. At opening of the right bile duct, small stones were found and removed. Antecolic Roux-en-Y hepaticojejunostomy then was performed. RESULTS: The operative time was 335 min. Recovery was uneventful, and the patient was discharged on postoperative day 4. CONCLUSIONS: Robotic repair of bile duct injuries is feasible and safe, even when liver resection is necessary. This video may help oncologic surgeons to perform this complex procedure.
doi: https://doi.org/10.1245/s10434-019-07474-w
- Cytomorphology of intraductal papillary neoplasm of the biliary tract
Diagnostic cytopathology 2019 Sep;47(9):922-926
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31116517
Intraductal papillary neoplasms of the bile duct (IPNBs) are papillary epithelial proliferations with delicate fibrovascular cores within dilated bile ducts. They are thought to be premalignant lesions with potential to progress invasive tumors. To our knowledge, there are no prior descriptions of IPNB cytomorphology. A 58-year-old male presented with painless jaundice and elevated liver function tests was found to have an intraluminal mass within the left hepatic duct. A bile duct brushing diagnosed as “atypical cells present” showed a cellular specimen composed of papillary groups and linear strips of mostly cuboidal/columnar cells with mild atypia and vacuolated cytoplasm. A left hepatic lobectomy including extrahepatic bile ducts showed the mass consisted of papillary cores lined by pancreatobiliary-type epithelium with mild-to-severe atypia, consistent with IPNB with a focus suspicious for invasion. The cytomorphologic features described in the current case suggest intraductal papillary neoplasm but may not be specific since similar features could be seen in other bile duct tumors and even in nonneoplastic conditions such as stent or cholelithiasis. However, it is worthwhile to report papillary hyperplasia with atypia in common bile duct brushings in order to avoid a false-negative diagnosis, especially in the context of a filling defect by images which does not appear to be a stone.
doi: https://doi.org/10.1002/dc.24212
- Acute Methamphetamine-Induced Hepatic and Pancreatic Ischemia
The American journal of forensic medicine and pathology 2019 Sep;40(3):285-288
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31033491
Methamphetamine is a central nervous system stimulant that induces arousal, a positive mood, cardiac stimulation, and an acute improvement in cognitive domains. Its illicit exploitation is rapidly growing in North America. Typically, extended use of the drug induces organ damage via vasoconstriction and subsequent ischemia. This case specifically discusses hepatic and pancreatic pathology resulting from methamphetamine overdose alongside an unusual discovery of globally necrotic von Meyenburg complexes.
doi: https://doi.org/10.1097/PAF.0000000000000486
- Response to the Letter to the Editor “Minimally Invasive Versus Open Distal Pancreatectomy (LEOPARD)”
Annals of surgery 2019 Aug;():
PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=31425333
doi: https://doi.org/10.1097/SLA.0000000000003541